Vitronectin receptor anatagonists, their preparation and their use

ABSTRACT

The present invention relates to compounds of the formula I, 
     
       
         A—B—D—E—F—G  (I) 
       
     
     in which A, B, D, E, F and G have the meanings given in the patent claims, to their preparation and to their use as medicaments. The compounds of the invention are used as vitronectin receptor antagonists and as inhibitors of bone resorption.

This is a divisional application of Ser. No. 08/995,522, filed Dec. 22,1997, now U.S. Pat. No. 5,990,145.

The present invention relates to compounds of the formula I

A—B—D—E—F—G  (I)

in which A, B, D, E, F and G have the meanings given below, theirphysiologically tolerated salts and pharmaceutical preparationscomprising these compounds, and to their preparation and use asvitronectin receptor antagonists for the treatment and prophylaxis ofdiseases which are based on the interaction between vitronectinreceptors and their ligands in cell-cell or cell-matrix interactionprocesses, for example inflammations, cancer, tumor metastasis,cardiovascular disorders such as arteriosclerosis or restenosis,retinopathies and nephropathies, and diseases which are based on anundesirable degree of bone resorption, for example osteoporosis.

Human bones are subject to a continuous, dynamic process ofreconstruction involving bone resorption and bone synthesis. Theseprocesses are regulated by cell types which are specialized for thesepurposes. While bone synthesis is based on the deposition of bone matrixby osteoblasts, bone resorption is based on the degradation of bonematrix by osteoclasts. Most bone disorders are based on an imbalance inthe equilibrium between bone formation and bone resorption. Osteoporosisis characterized by a loss of bone matrix. Activated osteoclasts aremultinuclear cells which have a diameter of up to 400 μm and whichdemolish bone matrix. Activated osteoclasts become attached to thesurface of the bone matrix and secrete proteolytic enzymes and acidsinto the so-called sealing zone, i.e. the region between their cellmembrane and the bone matrix. The acid environment and the proteasesdegrade the bone.

Studies have shown that the attachment of osteoclasts to bone isregulated by integrin receptors on the surface of the osteoclast cells.

Integrins are a superfamily of receptors which includes, inter alia, thefibrinogen receptor α_(IIb)β₃ on the blood platelets and the vitronectinreceptor α_(v)β₃. The vitronectin receptor α_(v)β₃ is a membraneglycoprotein which is expressed on the surface of a number of cells suchas endothelial cells, cells of the smooth musculature of the bloodvessels, osteoclasts and tumor cells. The vitronectin receptor α_(v)β₃which is expressed on the osteoclast membrane regulates the process ofattachment to bone and bone resorption and consequently contributes toosteoporosis. In this connection, α_(v)β₃ binds to bone matrix proteins,such as osteopontin, bone sialoprotein and thrombospontin, which containthe tripeptide motif Arg-Gly-Asp (or RGD).

As vitronectin receptor antagonists, the novel compounds of the formulaI inhibit bone resorption by osteoclasts. Bone disorders for which thenovel compounds can be employed are, in particular, osteoporosis,hypercalcaemia, osteopenia, e.g. caused by metastases, dental disorders,hyperparathyroidism, periarticular erosions in rheumatoid arthritis, andPaget's disease. In addition, the compounds of the formula I may beemployed for the alleviation, avoidance or therapy of bone disorderswhich are caused by glucocorticoid, steroid or corticosteroid therapy orby a lack of sex hormone(s). All these disorders are characterized by aloss of bone, due to an imbalance between bone synthesis and bonedegradation.

Horton and coworkers describe RGD peptides and an anti-vitronectinreceptor antibody (23C6) which inhibit tooth breakdown by osteoclastsand the migration of osteoclasts (Horton et al.; Exp. Cell. Res. 1991,195, 368). In J. Cell Biol. 1990, 111, 1713, Sato et al. report thatechistatin, an RGD peptide from snake venom, is a potent inhibitor ofbone resorption in a tissue culture and an inhibitor of the attachmentof osteoclasts to the bone. Fischer et al. (Endocrinology, 1993, 132,1411) showed that echistatin also inhibits bone resorption in vivo inthe rat.

The vitronectin receptor α_(v)β₃ on human cells of the smooth bloodvessel musculature of the aorta stimulates the migration of these cellsinto the neointima, thereby leading finally to arteriosclerosis andrestenosis following angioplasty (Brown et al., Cardiovascular Res.1994, 28, 1815).

Brooks et al. (Cell 1994, 79,1157) show that antibodies against α_(v)β₃or α_(v)β₃ antagonists are able to shrink tumors by inducing theapoptosis of blood vessel cells during angiogenesis. Cheresh et al.(Science 1995, 270, 1500) describe antiα_(v)β₃ antibodies or α_(v)β₃antagonists which inhibit bFGF-induced angiogenesis processes in the rateye, a property which could be therapeutically useful in the treatmentof retinopathies.

Patent application WO 94/12181 describes substituted aromatic ornonaromatic ring systems, and WO 94/08577 describes substitutedheterocycles, which are fibrinogen receptor antagonists and inhibitorsof platelet aggregation. EP-A0 528 586 and EP-A0 528 587 disdoseaminoalkyl-substituted or heterocyclyl-substituted phenylalaninederivatives, and WO 95/32710 discloses aryl derivatives, which areinhibitors of bone resorption due to osteoclasts. WO 96/00574 and WO96126190 describe benzodiazepines which are vitronectin receptorantagonists and integrin receptor antagonists, respectively. WO 96/00730describes fibrinogen receptor antagonist templates, in particularbenzodiazepines which are linked to a nitrogen-arrying 5-membered ring,which are vitronectin receptor antagonists. German patent applications P19629816.4, P 19629817.2 and P 19610919.1 and also EP-A-0 796 855describe substituted aromatic ring systems or 5-membered ringheterocycles which are vitronectin receptor antagonists.

The present invention relates to compounds of the formula I,

A—B—D—E—F—G  (I)

in which:

A is

is a 5-membered to 10-membered monocyclic or polycyclic, aromatic ornonaromatic ring system which can contain from 1 to 4 heteroatoms fromthe group N, O and S and can optionally be substituted, once or morethan once, by R¹², R¹³, R¹⁴ and R¹⁵;

B is a direct linkage, (C₁-C₈)-alkanediyl, (C₅-C₁₀)-arylene,(C₃-C₈)-cycloalkylene, —C≡C—, —NR²—, —NR²—C(O)—, —NR²—C(O)—NR²—,—NR²—C(S)—NR²—, —O—C(O)—, —NR²—S(O)—, —NR²—S(O)₂—, —O—, —S— or—CR²═CR³—, which can in each case be substituted, once or twice, by(C₁-C₈)-alkyl, for example -methyl-phenyl-methyl-, -ethyl-NR²—C(O)—etc.;

D is a direct linkage, (C₁-C₈)-alkanediyl, (C₅-C₁₀)-arylene, —O—, —NR²—,—CO—NR²—, —NR²—CO—, —NR²—C(O)—NR²—, —NR²—C(S)—NR²—, —OC(Q)—, —C(O)O—,—S(O)—, —S(O)2—, —S(O)₂—NR²—, —S(O)—NR²—, —NR²—S(O)—, —NR²—S(O)₂—, —S—,—CR²═CR³— or —C≡C— which can in each case be substituted, once or twice,by (C₁-C₈)-alkyl, —CR²═CR³— or (C₅-C₆)-aryl, for examplemethyl-phenyl-CH═CH—, ethyl-O— etc., with it not being possible for D tobe —CO—NR²—, —C(O)O—, —S(O)—, —S(O)₂—, —S(O)—NR²— or —S(O)₂—NR²— when Bis a direct linkage;

E a) is a template which is selected from the series of fibrinogenreceptor antagonists and which is taken from the following patentapplications, patent documents or literature references:

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or

b) is a template which is defined analogously to the templates from theseries of fibrinogen receptor antagonists and which is taken from thefollowing patent applications:

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or also is one of those templates which can be derived structurally fromthe templates which are described in the above patent applications,patent documents and publications;

F is defined like D;

R² and R³ are, independently of each other, H, (C₁-C₁₀)-alkyl, which isoptionally substituted, once or more than once, by fluorine,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, (C₅-C₁₄)-aryl,(C₅-C₁₄)-aryl, (C₁-C₈)-alkyl, R⁸OC(O)R⁹, R⁸R⁸NC(O)R⁹ or R⁸C(O)R⁹;

R⁴, R⁵, R⁶ and R⁷ are, independently of each other, H, fluorine, OH,(C₁-C₈)-alkyl, (C₃-C₁₄)-cycloalkyl, (C₃-C₁₄)-cycloalkyl-(C₁-C₈)-alkyl,or R⁸OR⁹, R⁸SR⁹, R⁸CO₂R⁹, R⁸OC(O)R⁹, R⁸—C₅-C₁₄)-aryl-R⁹, R⁸N(R²)R⁹,R⁸R⁸NR⁹, R⁸N(R²)C(O)OR⁹, R⁸S(O)_(n)N(R²)R⁹, R⁸OC(O)N(R²)R⁹,R⁸C(O)N(R²)R⁹, R⁸N(R²)C(O)N(R²)R⁹, R⁸N(R²)S(O)_(n)N(R²)R⁹, R⁸S(O)_(n)R⁹,R⁸SC(O)N(R²)R⁹, R⁸C(O)R⁹, R⁸N(R²)C(O)R⁹ or R⁸N(R²)S(O)_(n)R⁹;

R⁸ is H, (C₁-C₈)-alkyl, (C₃-C₁₄)-cycloalkyl,(C₃-C₁₄)-cycloalkyl-(C₁-C₈)-alkyl, (C₅-C₁₄)-aryl or(C₅-C₁₄)-aryl-(C₁-C₈)-alkyl, where the alkyl radicals can besubstituted, once or more than once, by fluorine;

R⁹ is a direct linkage or (C₁-C₈)-alkanediyl;

R¹⁰ is C(O)R¹¹, C(S)_(n)R¹¹, S(O)R¹¹, P(O)(R¹¹)_(n), or a four-memberedto eight-membered, saturated or unsaturated heterocycle which contains1, 2, 3 or 4 heteroatoms from the group N, O and S, such as tetrazolyl,imidazolyl, pyrazolyl, oxazolyl or thiadiazolyl;

R¹¹ is OH, (C₁-C₈)-alkoxy, (C₅-C₁₄)-aryl-(C₁-C₈)-alkoxy,(C₅-C₁₄)-aryloxy, (C₁-C₈)-alkylcarbonyloxy-(C₁-C₄)-alkoxy,(C₅-C₁₄)-aryl-(C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxy, NH₂, mono- ordi-((C₁-C₈)-alkyl)-amino, (C₅-C₁₄)-aryl-(C₁-C₈)-alkylamino,(C₁-C₈)-dialkylaminocarbonylmethyloxy,(C₅-C₁₄)-aryl-(C₁-C₈)-dialkylaminocarbonylmethyloxy or(C₅-C₁₄)-arylamino or the radical of an L-amino acid or D-amino acid;

R¹², R¹³, R¹⁴ and R¹⁵ are, independently of each other, H,(C₁-C₁₀)-alkyl which is optionally substituted, once or more than once,by fluorine, (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl,(C₅-C₁₄)-aryl, (C₅-C₁₄)-aryl(C₁-C₈)-alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹,R⁹OC(O)R⁹, R⁸R⁸NR⁹, R⁸—C₅-C₁₄)-aryl-R⁹, HO—(C₁-C₈)-alkyl-N(R²)R⁹,R⁸N(R²)C(O)R⁹, R⁸C(O)N(R²)R⁹, R⁸C(O)R⁹, R²R³N—C(═NR²)—NR²,R²R³N—C(═NR²), ═O, or ═S;

where two adjacent substituents from R¹² to R¹⁵ can also together be—OCH₂O—, —OCH₂CH₂O— or —OC(CH₃)₂O—;

y is NR², O or S;

n is 1 or 2;

p and q are, independently of each other, 0 or 1;

in all their stereoisomeric forms and mixtures thereof in allproportions, and their physiologically tolerated salts,

with compounds being excepted in which E

a) is a 6-membered aromatic ring system which can contain up to 4 Natoms and which can be substituted by from 1 to 4 identical or differentarbitrary substituents, or

b) is 4-methyl-3-oxo-2,3,4,5-tetrahydro-1-H-1,4-benzodiazepine.

A template from the series of fibrinogen receptor antagonists isunderstood to mean the central part of the molecular structure (of afibrinogen receptor antagonist) to which, in the case of the fibrinogenreceptor antagonists, a basic group and an acidic group are linked byway of spacers, with the basic and/or acidic group being present inprotected form (prodrug) where appropriate.

In the fibrinogen receptor antagonists, the basic group is generally anN-containing group, such as amidine or guanidine, while the acidic groupis generally a carboxyl function, with it being possible for the basicgroup and the acidic group to be present in each case in protected form.

A fibrinogen receptor antagonist is an active compound which inhibitsthe binding of fibrinogen to the blood platelet receptor GPIIbIIIa.

A fibrinogen receptor antagonist comprises a central part (template) towhich a basic group and an acidic group are linked by way of spacers,with the basic group and/or acidic group being present in protected form(prodrug), where appropriate.

Alkyl radicals may be straight-chain or branched. This also applies ifthey carry substituents or appear as the substituents of other radicals,for example in alkoxy, alkoxycarbonyl or aralkyl radicals. Examples ofsuitable (C₁-C₁₀)-alkyl radicals are: methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, decyl, isopropyl, isopentyl, neopentyl,isohexyl, 3-methylpentyl, 2,3,5-trimethylhexyl, sec-butyl andtert-pentyl. Preferred alkyl radicals are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

Alkenyl and alkynyl radicals may also be straight-chain or branched.Examples of alkenyl radicals are vinyl, 1-propenyl, allyl, butenyl and3-methyl-2-butenyl, while examples of alkynyl radicals are ethynyl,1-propynyl or propargyl.

Cycloalkyl radicals may be monocyclic or polycyclic, e.g. bicyclic ortricyclic. Examples of monocyclic cycloalkyl radicals are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl andcyclododecyl which, however, can also be substituted by, for example,(C₁-C₄)-alkyl. 4-Methylcyclohexyl and 2,3-dimethylcyclopentyl may bementioned as examples of substituted cycloalkyl radicals.

Cyclodecane and cyclododecane are examples of parent substances of themonocyclic (C₁₀-C₁₄)-cycloalkyl radicals in R⁴, R⁵, R⁶ and R⁷.

Bicyclic and tricyclic cycloalkyl radicals may be unsubstituted orsubstituted, in any suitable position, by one or more oxo groups and/orone or more identical or different (C₁-C₄)-alkyl groups, e.g. methylgroups or isopropyl groups, preferably methyl groups. The free bond ofthe bicyclic or tricyclic radical can be located in any position in themolecule; the radical can consequently be bonded via a bridgehead atomor via an atom in a bridge. The free bond can also be located in anystereochemical position, for example in an exo position or an endoposition.

An example of a bicyclic ring system is decalin (decahydronaphthalene),while an example of a system substituted by an oxo group is 2-decanone.

Examples of parent substances of bicyclic ring systems are norbomane(=bicyclo[2.2.1]heptane), bicyclo[2.2.2]octane and bicyclo[3.2.1]octane.An example of a system which is substituted by an oxo group is camphor(=1,7,7-trimethyl-2-oxobicyclo[2.2.1]heptane).

Examples of parent substances of tricyclic systems are twistane(=tricyclo[4.4.0.0^(3,8)]decane, adamantane(=tricyclo[3.3.1.1^(3,7)]decane), noradamantane(=tricyclo[3.3.1.0^(3,7)]-nonane), tricyclo[2.2.1.0^(2,6)]heptane,tricyclo[5.3.2.0^(4,9)]dodecane, tricyclo[5.4.0.0^(2,9)]undecane ortricyclo[5.5.1.0^(3,11)]tridecane.

Examples of parent substances of tricyclic (C₁₀-C₁₄)-cycloalkyl radicalsin R⁴, R⁵, R⁶ and R⁷ are twistane (=tricyclo[4.4.0.0.^(3,8)]decane,adamantane (=tricyclo[3.3.1.1.^(3,7)]nonane),tricyclo[5.3.2.0^(4,9)]dodecane, tricyclo[5.4.0.0^(2,9)]undecane ortricyclo[5.5.1.0^(3,11)]tridecane.

Halogen is fluorine, chlorine, bromine or iodine.

Examples of 6-membered aromatic ring systems are phenyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl and tetrazinyl.

Aryl is, for example, phenyl, naphthyl, biphenylyl, anthryl orfluoroenyl, with 1-naphthyl, 2-naphthyl and, in particular, phenyl beingpreferred. Aryl radicals, in particular phenyl radicals, may besubstituted, once or more than once, preferably once, twice or threetimes, by identical or different radicals from the group consisting of(C₁-C₈)-alkyl, in particular (C₁-C₄)-alkyl, (C₁-C₈)-alkoxy, inparticular (C₁-C₄)-alkoxy, halogen, such as fluorine, chlorine andbromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy,—OCH₂CH₂O—, —OC(CH₃)₂O—, cyano, hydroxycarbonyl, aminocarbonyl,(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (R¹⁷O)₂P(O),(R¹⁷O)₂P(O)—O— or tetrazolyl, where R¹⁷ is H, (C₁-C₁₀)-alkyl,(C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl.

In monosubstituted phenyl radicals, the substituent can be located inthe 2, 3 or 4 position, with the 3 and 4 positions being preferred. Ifphenyl is substituted twice, the substituents can be in the 1, 2 or 1, 3or 1,4 positions relative to each other. The two substituents in phenylradicals which are substituted twice are preferably arranged in the 3and 4 position, based on the linkage site.

Aryl groups can also be monocyclic or polycyclic aromatic ring systemsin which from 1 to 5 carbon atoms can be replaced by from 1 to 5heteroatoms, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl,thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl,isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, cinnolinyl or β-carbolinyl, or abenzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative ofthese radicals. These heterocycles can be substituted by the samesubstituents as the abovementioned carbocyclic aryl systems.

Of these aryl groups, preference is given to monocyclic or bicyclicaromatic ring systems which have from 1 to 3 heteroatoms from the groupN, O and S and which can be substituted by from 1 to 3 substituentsselected from the group consisting of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, F,Cl, NO₂, NH₂, CF₃, OH, (C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy,benzyloxy or benzyl.

In this context, particular preference is given to monocyclic orbicyclic aromatic 5-membered to 10-membered ring systems which have from1 to 3 heteroatoms from the group N, O and S and which can besubstituted by from 1 to 2 substituents from the group consisting of(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

L- or D-amino acids can be natural or unnatural amino acids. α-Aminoacids are preferred. The following may be mentioned by way of example(cf. Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Volume XV/1 and 2, Georg Thieme Verlag, Stuttgart, 1974):

Aad, Abu, γAbu, ABz, 2ABz, εAca, Ach, Acp, Adpd, Ahb, Aib, βAib, Ala,βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze,Azi, Bai, Bph, Can, Cit, Cys, (Cys)₂, Cyta, Daad, Dab, Dadd, Dap, Dapm,Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln,hGlu, His, hlle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr,Hyl, Hyp, 3Hyp, lle, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, βLys,ΔLys, Met, Mim, Min, nArg, Nle, Nva, Oly, Om, Pan, Pec, Pen, Phe, Phg,Pic, Pro, ΔPro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi,βThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val,tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine(Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia),2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid and2-(p-chlorophenyl)aminoacetic acid;

and also:

pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid;1,2,3,4-tetra-hydroisoquinoline-3-carboxylic acid;decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylicacid; decahydroquinoline-2-carboxylic acid;octahydrocyclopentatblpyrrole-2-carboxylic acid;2-azabicyclo[2.2.2]octane-3-carboxylic acid;2-azabicyclo[2.2.1]heptane-3-carboxylic acid;2-azabicyclo[3.1.0]hexane-3-carboxylic acid;2-azaspiro[4.4]nonane-3-carboxylic acid;2-azaspiro[4.5]decane-3-carboxylic acid;spiro(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid;spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid;2-azatricyclo[4.3.0.1^(6,9)]decane-3-carboxylic acid;

decahydrocyclohepta[b]pyrrole-2-carboxylic acid;decahydrocycloocta[c]pyrrole-2-carboxylic acid;octahydrocyclopenta[c]pyrrole-2-carboxylic acid;octahydroisoindole-1-carboxylic acid;2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid;2,3,3a,4,5,7a-hexahydmindole-2-carboxylic acid;tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid;pyrazolidine-3-carboxylic acid and hydroxypyrrolidine-2-carboxylic acid,all of which can optionally be substituted (see the following formulae):

The heterocycles on which the abovementioned radicals are based aredisclosed, for example, in U.S. Pat. No. 4,344,949; U.S. Pat. No.4,374,847; U.S. Pat. No. 4,350,704; EP-A 29,488; EP-A 31,741; EP-A46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870;EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A105,102; EP-A 109,020; EP-A 111,873; EP-A 271,865 and EP-A 344,682.

In addition, the amino acids can also be present as esters or amides,such as methyl esters, ethyl esters, isopropyl esters, isobutyl esters,tert-butyl esters, benzyl esters, unsubstituted amide, ethylamide,semicarbazide or ω-amino-(C₂-C₈)-alkylamide.

Functional groups of the amino acids may be present in protected form.Suitable protecting groups, such as urethane protecting groups, carboxylprotecting groups and side-chain protecting groups, are described inHubbuch, Kontakte (Merck) 1979, No. 3, pages 14 to 23 and in Büllesbach,Kontakte (Merck) 1980, No. 1, pages 23 to 35. Those which may, inparticular, be mentioned are: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz,Bpoc, Adoc, Msc, Moc, Z(NO₂), Z(Hal_(n)), Bobz, lboc, Adpoc, Mboc, Acm,tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.

Physiologically tolerated salts of the compounds of the formula I are,in particular, pharmaceutically utilizable or nontoxic salts. Such saltsare formed, for example, from compounds of the formula I which containacidic groups, e.g. carboxyl, with alkali metals or alkaline earthmetals, such as Na, K, Mg and Ca, and also with physiologicallytolerated organic amines, such as triethylamine, ethanolamine ortris-2-hydroxyethyl)amine. Compounds of the formula I which containbasic groups, e.g. an amino group, an amidino group or a guanidinogroup, form salts with inorganic acids, such as hydrochloric acid,sulfuric acid or phosphoric acid, and with organic carboxylic acids orsulfonic acids, such as acetic acid, citric acid, benzoic add, maleicacid, fumaric add, tartaric acid, lactic acid, methanesulfonic acid orp-toluenesulfonic acid.

The novel compounds of the formula I may contain optically active carbonatoms, which, independently of each other, can have R or Sconfigurations, and they consequently may be present in the form of pureenantiomers or pure diastereomers or in the form of enantiomericmixtures or diastereomeric mixtures. The present invention relates bothto pure enantiomers and enantiomeric mixtures in all proportions and todiastereomers and diastereomeric mixtures in all proportions.

The novel compounds of the formula I may be present, independently ofeach other, as E/Z isomeric mixtures. The present invention relates bothto pure E and Z isomers and to E/Z isomeric mixtures. Diastereomers,including E/Z isomers, can be separated into the individual isomers bymeans of chromatography. Racemates can be separated into the twoenantiomers either by means of chromatography on chiral phases or bymeans of racemate resolution.

In addition to this, the novel compounds of the formula I may containmobile hydrogen atoms, that is they may be present in differenttautomeric forms. The present invention also relates to all thesetautomers.

The present invention moreover includes all solvates of compounds of theformulae I and Ia, for example hydrates or adducts with alcohols, andalso derivatives of the compounds of the formulae I and Ia, for exampleesters, prodrugs and metabolites, which act like the compounds of theformulae I and Ia.

Preference is given to compounds of the formula I which are selectivevitronectin receptor antagonists, particularly in relation to thefibrinogen receptor, i.e. which are stronger inhibitors of thevitronectin receptor than of the fibrinogen receptor.

Preference is given, in particular, to compounds of the formula I whichare selective vitronectin receptor antagonists and in which the distancebetween R¹⁰ and the first N atom in A is from 12 to 13 covalent bondsalong the shortest route between these atoms, as depicted below, by wayof example, for

and R¹⁰=COOH:

Preference is also given to compounds of the formula I in which at leastone radical from the group R⁴, R⁵, R⁶ and R⁷ is a lipophilic radical.

Examples of lipophilic radicals in the group R⁴, R⁵, R⁶ and R⁷ areneopentyl, cyclohexyl, adamantyl, cyclohexyl-C₁-C₈)-alkyl,adamantyl-(C₁-C₈)-alkyl, phenyl, naphthyl, phenyl-(C₁-C₈)-alkyl,naphthyl-C₁-C₈)-alkyl, cyclohexylmethylcarbonylamino,1-adamantylmethyloxycarbonylamino or benzyloxycarbonylamino, or,generally, radicals in which R⁸ is, for example, neopentyl, cyclohexyl,adamantyl, cyclohexyl-C₁-C₈)-alkyl, adamantyl-(C₁-C₈)-alkyl, phenyl,naphthyl or phenyl-(C₁-C₈)-alkyl.

Preference is furthermore given to compounds of the formula I in which:

A is the radical

is a 5-membered to 10-membered monocyclic or polycyclic, aromatic ornonaromatic ring system which can contain from 1 to 4 heteroatoms fromthe group consisting of N, O and S and which can optionally besubstituted, once or more than once, by R¹², R¹³, R¹⁴ and R¹⁵;

B is a direct linkage, (C₁-C₆)-alkanediyl, (C₅-C₈)-arylene,(C₃-C₈)-cycloalkylene, —C≡C—, —NR²—, —NR²—C(O)—, —NR²—C(O)—NR²—,—NR²—S(O)—, —NR²—S(O)₂—, —O— or —CR²═CR³— which can in each case besubstituted, once or twice, by (C₁-C₆)-alkyl;

D is a direct linkage, (C₁-C₈)-alkanediyl, (C₅-C₈)-arylene, —O—, NR²—,—CO—NR²—, —NR²—CO—, —NR²—C(O)—NR²—, —OC(O)—, —C(O)O—, —S(O)₂—,—S(O)₂—NR²—, —NR²—S(O)₂—, —S—, —CR²═CR³— or —C═C— which can in each casebe substituted, once or twice, by (C₁-C₈)-alkyl, —CR²═CR³— or(C₅-C₆)-aryl, with it not being possible for D to be —CO—NR²—, —C(O)O—,—SO₂— or —S(O)₂—NR²— when B is a direct linkage;

E is a template which is selected from the fibrinogen receptorantagonist group and which is taken from:

U.S. Pat. No. 5,250,679, Oct. 5, 1993, Blackburn, B. K. et al.

U.S. Pat. No. 5,403,836, Apr. 4, 1995, Blackburn, B. K. et al.

U.S. Pat. No. 5,565,449, Oct. 15, 1996, Blackburn, B. K. et al.

WO 93108174, Oct. 15, 1991, Blackburn, B. K. et al.

WO 95104057, Feb. 9, 1995, Blackburn, B. K. et al.

EP 0 655 439, Nov. 9, 1994, Denney, M. L. et al.

WO 94/18981, Sep. 1, 1994, Claremon, D. A. et al.

WO 94/08962, Apr. 28, 1994, Harmann, G. D. et al.

EP 0 668 278, Feb. 14, 1995, Juraszyk, H. et al.

WO 94/12478, Jun. 9, 1994, Keenan, E. Mc. C. et al.

F is defined like D;

R² and R³ are, independently of each other, H, (C₁-C₁₀)-alkyl, which isoptionally substituted, once or more than once, by fluorine,(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-C₁-C₆)-alkyl, (C₅-C₁₂)-aryl,(C₅-C₁₂)-aryl-C₁-C₆)-alkyl, R⁸OC(O)R⁹, R⁸R⁸NC(O)R⁹ or R⁸C(O)R⁹;

R⁴, R⁵, R⁶ and R⁷ are, independently of each other, H, fluorine, OH,(C₁-C₈)-alkyl, (C₅-C₁₄)-cydoalkyl, (C₅-C₁₄)-cycloalkyl-C₁-C₈)-alkyl, orR⁸OR⁹, R⁸SR⁹, R⁸CO₂R⁹, R⁸OC(O)R⁹, R⁸—(C₅-C₁₄)-aryl-R⁹, R⁸N(R²)R⁹,R⁸R⁸NR⁹, R⁸N(R²)C(O)OR⁹, R⁸S(O)_(n)N(R²)R⁹, R⁸OC(O)N(R²)R⁹,R⁸C(O)N(R²)R⁹, R⁸N(R²)C(O)N(R²)R⁹, R⁸N(R²)S(O)_(n)N(R²)R⁹, R⁸S(O)_(n)R⁹,R⁸SC(O)N(R²)R⁹, R⁸C(O)R⁹, R⁸N(R²)C(O)R⁹ or R⁸N(R²)S(O)_(n)R⁹;

R⁸ is H, (C₁-C₆)-alkyl, (C₅-C₁₄)-cycloalkyl,(C₅-C₁₄)-cycloalkyl-(C₁-C₆)-alkyl, (C₅-C₁₂)-aryl or(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl, where the alkyl radicals can besubstituted, once or more than once, by fluorine;

R⁹ is a direct linkage or (C₁-C₆)-alkanediyl;

R¹⁰ is C(O)R¹¹, C(S)R¹¹, S(O)_(n)R¹¹, P(O)(R¹¹)_(n) or a four-memberedto eight-membered, saturated or unsaturated heterocycle which contains1, 2, 3 or 4 heteroatoms from the group N, O and S;

R¹¹ is OH, (C₁-C₆)-alkoxy, (C₅-C₁₂)-aryl-(C₁-C₆)-alkoxy,(C₅-C₁₂)-aryloxy, (C₁-C₆)-alkylcarbonyloxy-(C₁-C₄)-alkoxy,(C₅-C₁₂)-aryl-(C₁-C₆)-alkylcarbonyloxy-(C₁-C₆)-alkoxy, NH₂, mono- ordi-((C₁-C₆)-alkyl)-amino, (C₅-C₁₂)-aryl-(C₁-C₆)-alkylamino,(C₁-C₆)-dialkylaminocarbonylmethyloxy;

R¹², R¹³, R¹⁴ and R¹⁵ are, independently of each other, H, (C₁-C₈)-alkylwhich is optionally substituted, once or more than once, by fluorine,(C₃-C₈)-cycloalkyl, (C₃-C₈)-cloalkyl-(C₁-C₆)-alkyl, (C₅-C₁₂)-aryl,(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹, R⁸OC(O)R⁹,R⁸—C₅-C₁₂)-aryl-R⁹, R⁸R⁸NR⁹, HO—(C₁-C₈)-alkyl-N(R²)R⁹, R⁸N(R²)C(O)R⁹,R⁸C(O)N(R²)R⁹, R⁸C(O)R⁹, R²R³N—C(═NR²), R²R³N—C(═NR²)—NR², ═O or ═S;

where two adjacent substituents from R¹² to R¹⁵ can also together be—OCH₂O—, —OCH₂CH₂O— or —OC(CH₃)₂O—;

Y is NR², O or S;

n is 1 or 2;

p and q are, independently of each other, 0 or 1;

in all their stereoisomeric forms and mixtures thereof in allproportions, and their physiologically tolerated salts.

Particular preference is given to compounds of the formula I in which:

A is one of the radicals

B is a direct linkage, (C₁-C₆)-alkanediyl, (C₅-C₆)-arylene,(C₅-C₆)-cycloalkylene, —C≡C—, —NR²—, —NR²—C(O)—, —NR²S(O)₂—, —O— or—CR²═CR³—, which can in each case be substituted, once or twice, by(C₁-C₆)-alkyl;

D is a direct linkage, (C₁-C₆)-alkanediyl, (C₅-C₆)-arylene, —O—, —NR²—,—NR²—C(O)—, —C(O)NR²—, —NR²—C(O)—NR²—, —OC(O)—, —S(O)₂—NR²—, —NR²—S(O)₂—or —CR²═CR³— which can in each case be substituted, once or twice, by(C₁-C₆)-alkyl, with it not being possible for D to be —C(O)NR²— or—S(O)₂—NR²— when B is a direct linkage;

E a) is a template from WO 93108174, U.S. Pat. No. 5,250,679, U.S. Pat.No. 5,403,836 or U.S. Pat. No. 5,565,449, specifically:

where R^(1a), R^(2a), R^(20a), R^(21a) and R^(22a) are defined like R¹,R², R²⁰, R²¹ and R²² in U.S. Pat. No. 5,403,836, column 249, lines 9-22;and column 252, line 66 to column 253, line 68, and consequently:

R^(1a) and R^(2a) are, independently of each other, from one to threegroups from the series consisting of hydrogen, halogen, cyano,carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido,thioureido, hydroxyl, mercapto or sulfonamido, or an optionallysubstituted radical from the group consisting of C₁-C₁₂-alkyl,C₂-C₁₂-alkenyl, C₃-C₁₂-alkynyl, C₃-C₁₂-cycloalkyl, C₆-C₁₄-aryl,C₆-C₁₀-aryl-C₁-C₈-alkyl, C₁-C₁₂-alkyloxy-C₆-C₁₄-aryloxy andC₁-C₁₂-acylamino, where the substituents are a radical from the groupconsisting of halogen, cyano, azido, nitro, hydroxyl, mercapto,sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy,formyl, C₁-C₄-alkoxy, phenyl and phenoxy;

R^(20a) is hydrogen, halogen (fluorine, chlorine, bromine or iodine),C₁-C₄-alkoxy, C₁-C₄-alkyl, phenyl, benzyl or halogen-C₁-C₄-alkyl,

R^(21a) and R^(22a) are, independently of each other,

1. hydrogen

2. (C₁-C₁₂)-alkyl

3. (C₆-C₁₄)-aryl,

4. (C₃-C₁₄)-cycloalkyl,

5. (C₁-C₁₂)-alkyl-C₆-C₁₄)-aryl,

6. (C₁-C₁₂)-alkyl-C₃-C₁₄)-cycloalkyl, where the radicals defined under2. to 6. can be substituted by one or more radicals from the groupconsisting of

halogen (fluorine, chlorine, bromine or iodine); nitro; hydroxyl;carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide;phosphonate; C₁-C₆-alkyl; C₆-C₁₄-aryl; benzyl; C₃-C₁₄-cycloalkyl;COR^(24a) or CONR²⁵R²⁶; where

R^(24a) is a radical from the group consisting of C₁-C₈-alkoxy;C₃-C₁₂-alkenoxy; C₆-C₁₂-aryloxy; di-C₁-C₈-alkylamino-C₁-C₈-alkoxy;acylamino-C₁-C₈-alkoxy, such as acetylaminoethoxy,nicotinoylaminoethoxy, succinamidoethoxy or pivaloylethoxy; orC₆-C₁₂-aryl-C₁-C₈-alkoxy, where the aryl group can be optionallysubstituted by from one to three radicals selected from the groupconsisting of nitro, halogen, C₁-C₄-alkoxy, amino, hydroxyl,hydroxy-C₂-C₈-alkoxy or dihydroxy-C₃-C₈-alkoxy;

R²⁵ and R²⁶ are, independently of each other, hydrogen, C₁-C₁₀-alkyl,C₃-C₁₀-alkenyl, C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, or

R²⁵ and R²⁶ together form a trimethylene, tetramethylene, pentamethyleneor 3-oxopentamethylene radical;

7. Q²—L³, where

Q² is hydrogen or Q¹; and

L³ is a chemical bond, L¹ or L²;

Q¹ is a substituted or unsubstituted, positively charged,nitrogen-containing radical,

L¹ is a divalent radical which contains from 3 to 9 methylene groups,where from one to all the methylene groups can be replaced with one ormore alkene groups, alkyne groups, aryl groups or functional groupscontaining heteroatoms from the group consisting of N, O or S, and

L² is an optionally substituted, divalent radical;

where preferred radicals for Q¹, L¹ and L² are those radicals asdescribed in U.S. Pat. No. 5,403,836 in column 249, line 27 to column251, line 6 (Q¹), column 251, line 7 to column 252, line 18 (L¹) andcolumn 252, lines 19-45 (L²);

and R^(22b) is defined like R²² in U.S. Pat. No. 5,565,449, column 296,line 38 to column 297, line 38, and is:

1. hydrogen

2. (C₁-C₁₂)-alkyl

3. (C₆-C₁₄)-aryl,

4. (C₃-C₁₄)-cycloalkyl,

5. (C₁-C₁₂)-alkyl-(C₆-C₁₄)-aryl,

6. (C₁-C₁₂)-alkyl-(C₃-C₁₄)-cycloalkyl, where the radicals defined under2. to 6. can be substituted by one or more radicals from the groupconsisting of

halogen (fluorine, chlorine, bromine or iodine); nitro; hydroxyl;carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide;phosphonate; C₁-C₆-alkyl; C₆-C₁₄-aryl; benzyl; C₃-₁₄-cycloalkyl;COR^(24a) or CONR²⁵R²⁶; where

R^(24a) is a radical from the group consisting of C₁-C₈-alkoxy;C₃-C₁₂-alkenoxy; C₆-C₁₂-aryloxy; di-C₁-C₈-alkylamino-C₁-C₈-alkoxy;acylamino-C₁-C₈-alkoxy, such as acetylaminoethoxy,nicotinoylaminoethoxy, succinamidoethoxy or pivaloylethoxy; orC₆-C₁₂-aryl-C₁-C₈-alkoxy, where the aryl group can optionally besubstituted by from one to three radicals selected from the groupconsisting of nitro, halogen, C₁-C₄-alkoxy, amino, hydroxyl,hydroxy-C₂-C₈-alkoxy or dihydroxy-C₃-C₈-alkoxy;

R²⁵ and R²⁶ are, independently of each other, hydrogen, C₁-C₁₀-alkyl,C₃-C₁₀-alkenyl, C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, or

R²⁵ and R²⁶ together form a trimethylene, tetramethylene, pentamethyleneor 3oxopentamethylene radical;

7. Q²—L³ where

Q² is hydrogen or Q¹; and

L³ is a chemical bond, L¹ or L²;

Q¹ is a substituted or unsubstituted, positively charged,nitrogen-ontaining radical,

L¹ is a divalent radical which contains from 3 to 9 methylene groups,where from one to all the methylene groups can be replaced with one ormore alkene radicals, alkyne radicals, aryl radicals or functionalgroups containing heteroatoms from the group consisting of N, O or S,and

L² is an optionally substituted, divalent radical;

where preferred radicals for Q¹, L¹ and L² are those radicals asdescribed in U.S. Pat. No. 5,403,836 in column 289, line 9 to column293, line 17 (Q¹), column 293, line 18 to column 295, line 28 (L¹) andcolumn 295, line 29 to column 296, line 11 (L²);

or b) is a template from WO 95/04057, specifically:

where R^(1b) and R^(2b) are defined like R¹ and R² in U.S. Pat. No.5,403,836, column 249, lines 9-22; and:

R^(1b) and R^(2b) are, independently of each other, from one to threegroups from the series consisting of hydrogen, halogen, cyano,carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido,thioureido, hydroxyl, mercapto or sulfonamido, or an optionallysubstituted radical from the group consisting of C₁-C₁₂-alkyl,C₂-C₁₂-alkenyl, C₃-C₁₂-alkynyl, C₃-C₁₂-cycloalkyl, C₆-C₁₄-aryl,C₆-C₁₀-aryl-C₁-C₈-alkyl, C₁-C₁₂-lkyloxy,C₆-C₁₄-aryloxy andC₁₂-acacylamino, where the substituents are a radical from the groupconsisting of halogen, cyano, azido, nitro, hydroxyl, mercapto,sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy,formyl, C₁-C₄-alkoxy, phenyl and phenoxy; and

R^(25b) and R^(26b) are defined like R²⁵ and R²⁶ in U.S. Pat. No.5,565,449 and:

R^(25b) and R^(26b) are, independently of each other, hydrogen,C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, or

R^(25b) and R^(26b) together form a trimethylene, tetramethylene,pentamethylene or 3-oxopentamethylene radical;

or c)

is a template from EP-A 0 655 439, specifically

where

(R₂)_(p) is bonded to one or more carbon atoms of the 6-membered ringand is, independently of each other, a radical from the group consistingof H, alkyl, halogen-substituted alkyl, hydroxyalkyl, alkenyl, alkynyl,cycloalkyl, aryl, aryloxy, aralkyl, hydroxyl, alkoxy, aralkoxy,carbamyl, amino, substituted amino, acyl, cyano, halogen, nitro andsulfo;

R is (C₁-C₄)-alkyl

p is an integer from 1 to 3,

or d)

is a template from WO 94/12478, specifically

where R^(3′) is hydrogen, (C₁-C₆)-alkyl or aryl-C₁-C₆-alkyl,

or e) is a template from WO94/18981, specifically

in which V is CR^(7a) or N, and

D^(a) is CH₂, CH₂—CH₂, CH₂C(R^(7a))₂CH₂ or

in which X is CR^(3a) or N,

where R^(3a) is CN, C(O)N(R^(7a))R^(8a),

in which V is CR^(7a) or N, and

D^(a) is CH₂, CH₂—CH₂, CH₂C(R^(7a))₂CH₂ or

in which X is CR or N, in which

R^(3a) is CN, C(O)N(R^(7a))R^(8a),

where Y³ is O or H₂, and

R^(7a) is hydrogen; C₁-C₄-alkyl which is optionally substituted by OH or(C₁-C₄)-alkoxcy; C₂-C₆-alkenyl which is optionally substituted by(C₁-C₄)-alkoxy; or OH (C₁-C₄)-alkylaryl; or aryl which is optionallysubstituted by identical or different radicals from the group consistingof halogen, (C₁-C₄)-alkoxy, hydroxyl or (C₁-C₄)-alkyl,

R^(8a) is hydrogen or C₁-C₄-alkyl,

n is an integer from 0 to 7, and

n′ is an integer from 0 to 3;

or f) is a template from EP-A 0531 883, specifically

where:

X′ is an oxygen, sulfur or nitrogen atom or an —NR^(2b)-group, where

R^(2b) is a hydrogen atom, a straight-chain or branched alkyl grouphaving from 1 to 15 carbon atoms, a straightchain or branched alkenyl oralkynyl group having in each case from 3 to 10 carbon atoms, where thedouble bond or triple bond cannot connect directly to the nitrogen atom,a cycloalkyl or cycloalkylalkyl group having in each case from 3 to 7carbon atoms in the cycloalkyl moiety, an aryl group, an alkyl grouphaving from 2 to 6 carbon atoms which is substituted, from the βposition to the nitrogen atom of the —NR^(2b)-group onwards, by anR^(3b)O, (R^(3b))₂N—, R^(4b)CO—NR^(3b)—, alkylsulfonyl—NR^(3b)—,arylsulfonyl-NR^(3b)—, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl orR^(5b) group, or an alkyl group having from 1 to 6 carbon atoms which issubstituted by one or two aryl groups, R^(6b)OCO—, (R^(3b))₂NCO—,R^(5b)—CO—, R^(3b)O—CO-alkylene-NR₃—CO—,(R^(3b))₂NCO-alkylene—NR^(3b)—OC or R^(5b)CO-alkylene-NR^(3b)—CO-group,in which R^(3b) and R^(5b) are defined as indicated below and R^(6b) isa hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, acycloalkyl group having from 5 to 7 carbon atoms or an aralkyl group,

Y′ is an NO-group, a nitrogen atom or a methine group which isoptionally substituted by an alkyl group,

Z₁, Z₂, Z₃ and Z₄, which can be identical or different, are methinegroups, carbon atoms, imino groups or nitrogen atoms, where at least oneof the radicals Z₁ to Z₄ has to contain a carbon-atom, and one or twomethine groups which are adjacent to a nitrogen atom can in each case bereplaced by carbonyl groups,

Z₅ and Z₆ are in each case a carbon atom, or else one of the radicals Z₅or Z₆ is a nitrogen atom and the other of the radicals Z₅ or Z₆ is acarbon atom,

R^(3b) is a hydrogen atom, an alkyl group having from 1 to 6 carbonatoms, or an aryl, aralkyl, carboxyalkyl or alkoxycarbonylalkyl group,

R^(4b) is a hydrogen atom, an alkyl or alkoxy group having in each casefrom 1 to 6 carbon atoms, or an aryl or aralkyl group having from 1 to 6carbon atoms in the alkyl moiety, and

R^(5b) is an azetidino, pyrrolidino, hexamethylenimino orheptamethylenimino group or a piperidino group in which the methylenegroup in the 4 position can be replaced by an oxygen atom, by asulfenyl, sulfinyl or sulfonyl group, or by an imino group which issubstituted by an R₃, R₄CO—, alkylsulfonyl or arylsulfonyl group, whereR₃ and R₄ are defined as mentioned above;

F is a direct linkage, (C₁-C₆)-alkanediyl, —O—, —CO—NR²—, —NR²—CO—,—NR²—C(O)—NR²—, —OC(O)—, —C(O)O—, —CO—, —S(O)₂—, —S(O)₂—NR²—,—NR²—S(O)₂—, —CR²═CR³—, —C≡C— which can in each case be substituted,once or twice, by (C₁-C₆)-alkyl;

R² and R³ are, independently of each other, H, (C₁-C₆)-alkyl which isoptionally substituted, once or more than once, by fluorine,(C₅-C₆)-cycloalkyl, (C₅-C₆)-cloalkyl-(C₁-C₄)-alkyl, (C₅-C₁₀)-aryl,(C₅-C₁₀)-aryl-(C₁-C₄)-alkyl, R⁸OC(O)R⁹, R⁸R⁸NC(O)R⁹ or R⁸C(O)R⁹;

R⁴, R⁵, R⁶ and R⁷ are, independently of each other, H, fluorine, OH,(C₁-C₆)-alkyl, (C₅-C₁₄)-cycloalkyl, (C₅-C₁₄)-cycloalkyl-(C₁-C₆)-alkyl,or R⁸OR⁹, R⁸CO₂R⁹, R⁸OC(O)R⁹, R⁸—(C₅-C₁₀)-aryl-R⁹, R⁸NHR⁹, R⁸R⁸NR⁹,R⁸NHC(O)OR⁹, R⁸S(O)_(n)NHR⁹, R⁸OC(O)NHR⁹, R⁸C(O)NHR⁹, R⁸C(O)R⁹,R⁸NHC(O)NHR⁹, R⁸NHS(O)_(n)NHR⁹, R⁸NHC(O)R⁹ or R⁸NHS(O)_(n)R⁹, where atleast one radical from the group R⁴, R⁵, R⁶ and R⁷ is a lipophilicradical, such as benzyloxycarbonylamino, cyclohexylmethylcarbonylaminoetc.;

R⁸ is H, (C₁-C₆)-alkyl, (C₅-C₁₄)-cycloalkyl,(C₅-C₁₄)-cycloalkyl-C₁-C₄)-alkyl, (C₅-C₁₀)-aryl or(C₅-C₁₀)-aryl-C₁-C₄)-alkyl, where the alkyl radicals can be substitutedby from 1 to 6 fluorine atoms;

R⁹ is a direct linkage or (C₁-C₆)-alkanediyl;

R¹⁰ is C(O)R¹¹;

R¹¹ is OH, (C₁-C₆)-alkoxy, (C₅-C₁₀)-aryl-C₁-C₆)-alkoxy,(C₅-C₁₀)-aryloxy, (C₁-C₆)-alkylcarbonyloxy(C₁-C₄)-alkoxy,(C₅-C₁₀)-aryl-C₁-C₄)-alkylcarbonyloxy-C₁-C₄)-alkoxy, NH₂ or mono- ordi-(C₁-C₆)-alkyl)-amino;

R¹² is H, (C₁-C₆)-alkyl which is optionally substituted, once or morethan once, by fluorine, (C₃-C₆)-cylcloalkyl,(C₃-C₆)-cycloalkyl-C₁-C₄)-alkyl, (C₅-C₁₀)-aryl,(C₅-C₁₀)-aryl-C₁-C₄)-alkyl, H₂N, R⁸OR⁹, R⁸OC(O)R⁹, R⁸-(C₅-C₁₀)-aryl-R⁹,R⁸R⁸NR⁹, R⁸NHC(O)R⁹, R⁸C(O)NHR⁹, H₂N—C(═NH)—, H₂N—C(═NH)—NH— or ═O;

where two adjacent substituents R¹² can together also be —OCH₂O— or—OCH₂CH₂O—;

Y is NR², O or S;

n is 1 or 2; and

p and q are, independently of each other, 0 or 1;

in all their stereoisomeric forms and mixtures thereof in allproportions, and their physiologically tolerated salts.

Very particular preference is given to compounds of the formula I inwhich:

A is one of the radicals

B is a direct linkage, (C₁-C₄)-alkanediyl, phenylene, pyridindiyl,thiophenediyl, furandiyl, cyclohexylene, cyclopentylene, —C≡C— or—CR²═CR³— which can in each case be substituted, once or twice, by(C₁-C₄)-alkyl;

D is a direct linkage, (C₁-C₄)-alkanediyl or phenylene, —O—, —NR²—,—NR²—C(O)—, —C(O)—NR²—, —NR²—S(O)₂, —NR²—C(O)—NR²— or —CR²═CR³— whichcan in each case be substituted, once or twice, by (C₁-C₄)-alkyl, withit not being possible for D to be —C(O)—NR²— when B is a direct linkage;

E a) is a template from WO 93/08174, U.S. Pat. No. 5,250,679, U.S. Pat.No. 5,403,836 or U.S. Pat. No. 5,565,449, specifically:

where R^(1a), R^(20a), R^(21a), R^(22a) and R^(22b) are in this case:

R^(1a) is, independently of each other, from one to three groups fromthe series consisting of hydrogen and halogen (fluorine, chlorine,bromine or iodine);

R^(20a) is hydrogen;

R^(21a) and R^(22a) are, independently of each other,

1. hydrogen,

2. (C₁-C₆)-alkyl,

3. (C₆G₁₂)-aryl,

4. (C₆-C₁₂)-cycloalkyl,

5. (C₁-C₆)-akyl-C₆-C₁₂)-aryl,

6. (C₁-C₆)-akyl-C₆-C₁₂)-cyloalkyl, where the radicals defined under 2.to 6. can be substituted by one or more radicals from the groupconsisting of fluorine, chlorine, hydroxyl, hydroxamate, sulfonamide,(C₁-C₆)-alkyl, (C₆-C₁₂)-aryl, benzyl or (C₆-C₁₂)-cycloalkyl;

R^(22b) is

1. hydrogen,

2. (C₁-C₁₂)-alkyl,

3. (C₆-C₁₄)-aryl,

4. (C₃-C₁₄)-cycloalkyl,

5. (C₁-C₁₂)-alkyl-(C₆-C₁₄)-aryl,

6. (C₁-C₁₂)-alkyl-(C₃-C₁₄)-cycloalkyl, where the radicals defined under2. to 6. can be substituted by one or more radicals from the groupconsisting of

halogen (fluorine, chlorine, bromine or iodine); nitro; hydroxyl;carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide;phosphonate; C₁-C₆-alkyl; C₆-C₁₄-aryl; benzyl; C₃-C₁₄cycloalkyl;COR^(24a) or CONR²⁵R²⁶; where

R^(24a) is a radical from the group consisting of C₁-C₈-alkoxy;C₃-C₁₂-alkenoxy; C₆-C₁₂-aryloxy; di-C₁-C₈-alkylamino-C₁-C₈-alkoxy;acylamino-C₁-C₈-alkoxy, such as acetylaminoethoxy,nicotinoylaminoethoxy, succinamidoethoxy or pivaloylethoxy; orC₆-C₁₂-aryl-C₁-C₈-alkoxy, where the aryl group can be optionallysubstituted by from one to three radicals selected from the groupconsisting of nitro, halogen, C₁-C₄-alkoxy, amino, hydroxyl,hydroxy-C₂-C₈-alkoxy or dihydroxy-C₃-C₈-alkoxy;

R²⁵ and R²⁶ are, independently of each other, hydrogen, C₁-C₁₀-alkyl,C₃-C₁₀-alkenyl, C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, or

R²⁵ and R²⁶ together form a trimethylene, tetramethylene, pentamethyleneor 3-oxopentamethylene radical;

7. Q²—L³, where

Q² is hydrogen or Q¹; and

L³ is a chemical bond or L¹;

Q¹ is an amino, amidino, aminoalkylenimino, aminoalkylenamino orguanidino group, preferably an amidino group;

L¹ is C₆-C₁₄-aryl-C₂-C₄-alkynylene; C₆-C₁₄-aryl-C₁-C₃-alkylene;C₆-C₁₄-aryl-C₁-C₃-alkyloxyene or —R^(14c)—CO—NR^(6c)R^(15c), where

R^(6c) is hydrogen, C₁-C₄-alkoxy, C₁-C₄-alkyl or halogen-C₁-C₄-alkyl;

R^(14c) is a chemical bond, C₁-C₈-alkylene, C₃-C₇-cycloalkylene,C₂C₅-alkenylene, C₃-C₅-alkynylene, C₆-C₁₀-arylene,C₁3-alkyl-C₆-C₁₂-arylene, C₁-C₂-alkyl-C₆-C₁₀-aryl-C₁-C₂-alkylene,C₆-C₁₀-aryl-C₁-C₂-alkylene or C₆-C₁₀-aryloxy-C₁-C₂-alkylene, and

R^(15c) is a chemical bond, C₁-C₄-alkylen, C₂-C₄-alkenylen,C₂-C₄-alkynylen, C₆-C₁₀-arylen or C₁-C₃-alkyl-C₆4₁₂-arylen;

or b) is a template from WO 95/04057, specifically:

where R^(1b), R^(2b), R^(25b) and R^(26b) are in this case:

R^(1b) and R^(2b) are, independently of each other, from one to threegroups from the series consisting of hydrogen and halogen (fluorine,chlorine, bromine or iodine); and

R^(25b) and R^(26b) are, independently of each other, hydrogen,C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, orR^(25b) and R^(26b) together form a trimethylene, tetramethylene,pentamethylene or 3-oxopentamethylene radical;

or c) is a template from EP 0 655 439, specifically:

or d) is a template from WO 94/12478, specifically:

or e) is a template from WO 94/18981, specifically:

where Y³, V and D^(a) are defined as described above;

or f) is a template from EP 0 531 883, specifically:

where:

X′ is an oxygen, sulfur or nitrogen atom or an —NR^(2b)-group, where

R^(2b) is a hydrogen atom, a straight-chain or branched alkyl grouphaving from1 to 15 carbon atoms, a straight-chain or branched alkenyl oralkynyl group having in each case from 3 to 10 carbon atoms, where thedouble bond or triple bond cannot connect directly to the nitrogen atom,a cycloalkyl or cycloalkylalkyl group having in each case from 3 to 7carbon atoms in the cycloalkyl moiety, an aryl group, an alkyl grouphaving from 2 to 6 carbon atoms which is substituted, from the βposition to the nitrogen atom of the —NR^(2b)-group onward, by anR^(3b)O—, (R^(3b))₂N—, R^(4b)CO—NR^(3b)—, alkylsulfonyl—NR^(3b)—,aryisuffonyl-NR^(3b)—, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl orR^(5b) group, or an alkyl group having from 1 to 6 carbon atoms which issubstituted by one or two aryl groups, R^(6b)OCO—, (R^(3b))₂NCO—,R^(5b)—CO—, R^(3b)O—CO-alkylene-NR^(3b)—CO—,(R^(3b))₂N—CO-alkylene-NR^(3b)CO— or R^(5b)CO-alkylene-NR^(3b)—CO-group,in which R^(3b) and R^(5b) are defined as indicated below and R^(6b) isa hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, acycloalkyl group having from 5 to 7 carbon atoms or an aralkyl group,

Y is an NO-group, a nitrogen atom or a methine group which is optionallysubstituted by an alkyl group,

Z₁, Z₂, Z₃ and Z₄, which can be identical or different, are methinegroups, carbon atoms, imino groups or nitrogen atoms, where at least oneof the radicals Z₁ to Z₄ has to contain a carbon atom, and one or twomethine groups which are adjacent to a nitrogen atom can in each case bereplaced by carbonyl groups,

Z₅ and Z₆ are in each case a carbon atom, or else one of the radicals Z₅or Z₆ is a nitrogen atom and the other of the radicals Z₅ or Z₆ is acarbon atom,

R^(3b) is a hydrogen atom, an alkyl group having from 1 to 6 carbonatoms, or an aryl, aralkyl, carboxyalkyl or alkoxycarbonylalkyl group,

R^(4b) is a hydrogen atom, an alkyl or alkoxy group having in each casefrom 1 to 6 carbon atoms, or an aryl or aralkyl group having from 1 to 6carbon atoms in the alkyl moiety, and

R^(5b) is an azetidino, pyrrolidino, hexamethylenimino orheptamethylenimino group or a piperidino group in which the methylenegroup in the 4 position can be replaced by an oxygen atom, by asulfenyl, sulfinyl or sulfonyl group, or by an imino group which issubstituted by an R^(3b), R^(4b)CO—, alkylsulfonyl or arylsulfonylgroup, where R^(3b) and R^(4b) are defined as mentioned above,

F is a direct linkage, (C₁-C₆)-alkanediyl, —O—, —CO—NR²—, —NR²—CO—,—NR²—C(O)—NR²—, —S(O)₂—NR², —NR²—S(O)₂—, —CR²═CR³—, or —C≡C— which canin each case be substituted, once or twice, by (C₁-C₄)-alkyl;

G is

R² and R³ are, independently of each other, H, (C₁-C₄)-alkyl,trifluoromethyl, pentafluoroethyl, (C₅-C₆)-cycloalkyl,(C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl, phenyl or benzyl;

R⁴ is (C₁₀-C₁₄)-cycloalkyl, (C₁₀-C₁₄)-cycloalkyl-C₁-C₄)-alkyl, orR¹⁶OR⁹, R¹⁶NHR⁹, R¹⁶NHC(O)OR⁹, R¹⁶S(O)_(n)NHR⁹, R¹⁶OC(O)NHR⁹,R¹⁶C(O)NHR⁹, R¹⁶C(O)R⁹, R¹⁶NHC(O)R⁹ or R¹⁶NHS(O)_(n)R⁹;

R⁵ is H, (C₁-C₆)-alkyl, (C₅-C₆)-cycloalkyl,(C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl, trifluoromethyl, pentafluoroethyl,phenyl or benzyl;

R⁸ is H, (C₁-C₄)-alkyl, (C₅-C₆)-cycloalkyl,(C₅-C₆)-cycloalkyl-(C₁-C₂)-alkyl, phenyl, benzyl, trifluoromethyl orpentafluoroethyl;

R⁹ is a direct linkage or (C₁-C₄)-alkanediyl;

R¹⁰ is C(O)R¹¹;

R¹¹ is OH, (C₁-C₆)-alkoxy, phenoxy, benzyloxy,(C₁-C₄)-alkylcarbonyloxy-(C₁-C₄)-alkoxy, NH₂ or mono- ordi-((C₁-C₆)-alkyl)amino;

R¹² is H, (C₁-C₄)-alkyl, trifluoromethyl, pentafluoroethyl,(C₅-C₆)-cycloalkyl, (C₅-C₆)-cycloalkyl-(C₁-C₂)-alkyl, (C₅-C₆)-aryl,(C₅-C₆)-aryl-(C₁-C₂)-alkyl, H₂N, R⁸R⁸NR⁹, R⁸NHC(O)R⁹, H₂N—C(═NH) orH₂N—C(═NH)—NH—;

where two adjacent substituents R¹² can also be —OCH₂O— or —OCH₂CH₂O—;

R¹⁶ is (C₁₀-C₁₄)-cycloalkyl or (C₁₀-C₁₄)-cycloalkyl-(C₁-C₄)-alkyl whichcan optionally be substituted, once or twice, by (C₁-C₄)-alkyl,trifluoromethyl, phenyl, benzyl, (C₁-C₄)-alkoxy, phenoxy, benzyloxy, ═Oor mono- or di-((C₁-C₄)-alkyl)-amino, where the cycloalkylene radicalsare preferably 1-adamantyl or 2-adamantyl, which can be substituted asdescribed above;

n is 1 or 2; and

q is 0 or 1;

in all their stereoisomeric forms and mixtures thereof in allproportions, and their physiologically tolerated salts.

Preference is also given to compounds of the formula I, in which A, B,D, F and G are defined as above for the very particularly preferredcompounds of the formula I and E is a template from WO 95/04057, EP 0655439, WO 94/18981, WO 94/08962, EP 0668 278, WO 94/12478 or EP 0531 883,with the latter preferably being defined as above for the particularlypreferred compounds of the formula I, and particularly preferably beingdefined as above for the very particularly preferred compounds of theformula I.

Another part of the subject-matter of the present invention is that afibrinogen receptor antagonist, which is known per se, can be convertedinto a selective vitronectin receptor antagonist by replacing the basicgroup (with spacer) of a fibrinogen receptor antagonist with the residueA—B—D, which is defined as in Formula I, with the distance between R¹⁰and the first N atom in A being from 12 to 13 covalent bonds along theshortest route between these atoms.

In general, compounds of the formula I can be prepared, for exampleduring the course of a convergent synthesis, by linking two or morefragments which can be derived retrosynthetically from the formula I.When preparing the compounds of the formula I, it can, in a generalmanner, be necessary, during the course of the synthesis, to use aprotecting group strategy which is suited to the synthesis problem totemporarily block functional groups which could lead to undesirablereactions or side reactions in the particular synthesis step, as isknown to the skilled person. The method of fragment linking is notrestricted to the following examples but is generally applicable tosyntheses of the compounds of the formula I.

For example, compounds of the formula I of the type

A—B—D—E—C(O)NR²—G,

in which F=C(O)NR², can be prepared by condensing a compound of theformula II

A—B—D—E—M  II,

where M is hydroxycarbonyl, (C₁-C₆)-alkoxycarbonyl or activatedcarboxylic derivatives, such as acid chlorides, active esters or mixedanhydrides, with HNR²—G.

In order to condense two fragments with the formation of an amide bond,use is advantageously made of the coupling methods, which are known perse, of peptide chemistry (see, for example, Houben-Weyl, Methoden derOrganischen Chemie [Methods of Organic Chemistry], Volumes 15/1 and15/2, Georg Thieme Verlag, Stuttgart, 1974). For this, it is, as a rule,necessary for non-reacting amino groups which are present to beprotected with reversible protecting groups during the condensation. Thesame applies to carboxyl groups which are not involved in the reaction,which carboxyl groups are preferably employed as (C₁-C₆)-alkyl, benzylor tert-butyl esters. There is no necessity to protect amino groups ifthe amino groups to be generated are still present as nitro or cyanogroups and are only formed by means of hydrogenation after the couplinghas taken place. After the coupling has taken place, the protectinggroups which are present are eliminated in a suitable manner. Forexample, NO₂ groups (guanidino protection), benzyloxycarbonyl groups andbenzyl esters can be removed by hydrogenation. The protecting groups ofthe tert-butyl type are eliminated under acid conditions, while the9-flubrenylmethyloxycarbonyl radical is removed using secondary amines.

Compounds of the formula I in which R¹⁰=SO₂R¹¹ are prepared, forexample, by oxidizing compounds of the formula I in which R¹⁰=SH usingmethods which are known from the literature (cf. Houben-Weyl, Methodender Organischen Chemie, Vol. E12/2, Georg Thieme Verlag, Stuttgart 1985,pp. 1058 ff) to give compounds of the formula I in which R¹⁰=SO₃H, fromwhich the compounds of the formula I in which R¹⁰=SO₂R¹¹ (R¹¹≠OH) arethen prepared directly or by way of corresponding sulfonyl halides bymeans of esterification or formation of an amide bond.Oxidation-sensitive groups in the molecule, such as amino, amidino orguanidino groups, are, if necessary, protected with suitable protectinggroups before performing the oxidation.

Compounds of the formula I in which R¹⁰=S(O)R¹¹ are prepared, forexample, by converting compounds of the formula I in which R¹⁰=SH intothe corresponding sulfide (R¹⁰=S^(ø)) and then oxidizing withmeta-chloroperbenzoic acid to give the sulfinic acids (R¹⁰=SO₂H) (cf.Houben-Weyl, Methoden der Organischen Chemie, Vol. E11/1, Georg ThiemeVerlag, Stuttgart 1985, pp. 618 f), from which the correspondingsulfinic acid esters or amides, R¹⁰=S(O)R¹¹ (R¹¹≠OH), can be preparedusing methods which are known from the literature. In a general manner,other methods known from the literature can also be used to preparecompounds of the formula I in which R¹⁰=S(O)_(n)R¹¹ (n=1 or 2) (cf.Houben-Weyl, Methoden der Organischen Chemie, Vol. E11/1, Georg ThiemeVerlag, Stuttgart 1985, pp. 618 ff or Vol. E11/2, Stuttgart 1985, pp.1055 ff).

Compounds of the formula I in which R¹⁰=P(O)(R¹¹)n (n=1 or 2) aresynthesized, using methods which are known from the literature (cf.Houben-Weyl, Methoden der Organischen Chemie, Vols. E1 and E2, GeorgThieme Verlag, Stuttgart 1982), from suitable precursors, with it beingnecessary to match the selected synthesis method to the target molecule.

Compounds of the formula I in which R¹⁰=C(S)R¹¹ can be prepared usingmethods known from the literature (cf. Houben-Weyl, Methoden derOrganischen Chemie, Vols. E5/1 and E5/2, Georg Thieme Verlag, Stuttgart1985).

Compounds of the formula I in which R¹⁰=S(O)_(n)R¹¹ (n=1 or 2),P(O)(R¹¹)_(n) (n=1 or 2) or C(S)R¹¹ may, of course, also be prepared bymeans of fragment linking, as described above, which approach is, forexample, advisable when, for example, a (commercially available)aminosulfonic acid, aminosulfinic acid, aminophosphonic acid oraminophosphinic acid, or derivatives derived therefrom, such as estersor amides, are present in F—G of the formula I.

Compounds of the formula I in which A—B— is a radical of the formula

are prepared, using methods which are known from the literature, byreacting compounds of the formula

with sulfinic or sulfonic acid derivatives of the formula IV,

Q—S(O)_(n)—D—E—F—G  IV

in which Q is, e.g., Cl or NH₂, in analogy with S. Birtwell et al., J.Chem. Soc. (1946) 491 or Houben Weyl, Methoden der Organischen Chemie,Vol. E4, Georg Thieme Verlag, Stuttgart 1983; p. 620 ff.

Compounds of the formula I in which B is —NR²—C(O)—NR²—, —NR²—C(O)O— or—NR²—C(O)S— and A has the given meaning are prepared, for example, byreacting a compound of the formula V

 Q—D—E—F—G  V

in which Q is HNR²—, HO— or HS—, with a suitable carbonic acidderivative, preferably phosgene, diphosgene (trichloromethylchloroformate), triphosgene (bis(trichloromethyl) carbonate), ethylchloroformate, i-butyl chloroformate, bis(1-hydroxy-1-H-benzotriazolyl)carbonate or N,N′-carbonyidiimidazole in a solvent which is inerttowards the reagents employed, preferably dimethylformamide (DMF),tetrahydrofuran (THF) or toluene, at a temperature of between −20° C.and the boiling point of the solvent, preferably between 0° C. and 60°C., initially to form a substituted carbonic acid derivative of theformula VI,

in which R is —NR²—, —O— or —S— and Q′ is chlorine, methoxy, ethoxy,isobutoxy, benzotriazol-1-oxy or 1-imidazolyl, depending on the carbonicacid derivative employed.

The reaction of these derivatives with the monocycle orpolycycle-containing systems of the type VII

is effected in a protic or aprotic, polar but inert organic solvent. Inthis context, methanol, isopropanol or THF, at temperatures of from 20°C. up to the boiling temperature of these solvents, have proved to be ofvalue when reacting the methyl esters (Q=OMe) with the respectivecompounds of the formula VII. Most reactions of compounds of the formulaVI with salt-free compounds of the formula Vll are advantageouslycarried out in aprotic, inert solvents such as THF, dimethoxyethane ordioxane. However, when a base (such as NaOH) is employed, water can alsobe used as a solvent when compounds of the formula IV are reacted withthe compounds VII. When Q═Cl, the reaction is advantageously carried outwith the addition of a base as an acid-wpturing agent, in order to bindthe hydrohalic acid.

Compounds of the formula I in which F is —R²N—C(O)—NR²— or—R²N—C(S)—NR²—, are prepared, for example, by reacting a compound of theformula VIII

A—B—D—E—NHR²  VIII

with an isocyanate OCN—G or isothiocyanate SCN—G using methods which areknown from the literature.

Compounds of the formula I in which F is —C(O)NR²—, —SO₂NR²— or —(O)O—can be obtained, for example, by reacting

A—B—D—E—C(O)Q or A—B—D—E—SO₂Q

(Q is a leaving group which can readily be substituted nucleophilically,for example OH, Cl, OMe, etc.) with HR²N—G or HO—G, respectively, usingmethods known from the literature.

Compounds of the formula I, in which A is a monocycle or polycycle ofthe type

can be prepared, for example, by

a) reacting a compound of the formula IX

HR²N—D—E—F—G  IX

with a monocycle or polycycle of the type

in which X is a leaving group which can be substituted nucleophilically,for example halogen or SH, —SCH₃, SOCH₃, SO₂CH₃ or HN—NO2, using methodswhich are known from the literature (see, e.g., A. F. Mckay et al., J.Med. Chem. 6 (1963) 587, M. N. Buchman et al., J. Am. Chem. Soc. 71(1949), 766, F. Jung et al., J. Med. Chem. 34 (1991) 1110 or G. Sorba etal., Eur. J. Med. Chem. 21 (1986), 391),

or b) reacting a 1,2-diamino compound of the formula XVII

with an isothiocyanate of the formula XIII

SCN—B—D—E—F—G  XIII

to give a thiourea derivative of the formula XVIII

e.g. in accordance with F. Janssens et al., J. Med. Chem. 28 (1985)1925, which is then converted, as described in that paper or, forexample, in accordance with A.

Mohsen et al., Synthesis (1977) 864 or V. Ojka et al., Indian J. Chem.Sec. B 32 (3) (1993) 394, into the compounds of the formula I in which

or c) reacting a 1-nitro-2-amino compound of the formula XIX

with an isothiocyanate of the formula XIII to give a thiourea derivativeof the formula

which, after reduction of the nitrogroup with Pd/C (cf., e.g., F.Janssens et al., J. Med. Chem. 28 (1985) 1925) as described above, isconverted into compounds of the formula I in which

Compounds of the formula I in which A is a monocycle or polycycle of thetype

are obtained using methods which are known from the literature, e.g.from compounds of the formula

by reaction with compounds of the formula R²—NH—B—D—E—F—G following M.Yamato et al., Chem. Pharm. Bull 32(8) (1984) 3053, or, e.g., from1,2-aminoalcohols of the formula XII

which are initially converted, by reaction with isothiocyanates of theformula XIII

SCN—B—D—E—F—G  XIII

into thioureas of the formula XIV

which are then converted, e.g. as described by H. S. Chang et al., Chem.Lett. 8 (1986) 1291 or E. A. Ibrahim et al., J. Heterocycl. Chem. 19(4)(1982) 761, into the compounds of the formula I in which

Compounds of the formula I in which A is a monocycle or polycycle of thetype

are obtained using methods which are known from the literature, e.g.from 1,2-aminothiols of the formula XV

which are initially converted, by reaction with isothiocyanates of theformula XIII, into the thioureas of the formula XVI

which are then converted, e.g. as described by J. Garvin et al., J.Heterocycl. Chem. 28 (1991) 359 into the compounds of the formula I inwhich

Compounds of the formula I in which D is —C≡C— can be prepared, forexample, by reacting a compound of the formula X

X—E—F—G  X

in which X is I or Br, with a compound of the type A—B—C≡CH in apalladium-catalyzed reaction, as described, for example, in A. Arcadi etal., Tetrahedron Lett. 1993, 34, 2813 or E. C. Taylor et al., J. Org.Chem. 1990, 55, 3222.

In an analogous manner, compounds of the formula I in which F is —C≡C—can be prepared, for example, by linking compounds of the formula XI

A—B—D—E—X  XI

in which X is I or Br, with a compound of the type HC≡C—G in apalladium-catalyzed reaction.

The fibrinogen receptor antagonist template E is synthesized asdescribed in the relevant patents, patent applications or publications,with functional groups being incorporated into the template, or beingattached to the template, during synthesis of the template orafterwards, preferably during synthesis of the template, which groupspermit the subsequent linking-on of A—B—D and F—G by means of fragmentlinking, as described below, by way of example, for a template from WO94/18981:

Example of the linking-on of A—B—D and F—G

Preparation methods which are known from the literature are described,for example, in J. March, Advanced Organic Chemistry, Third Edition(John Wiley & Sons, 1985).

The compounds of the formula I, and their physiologically toleratedsalts, may be administered to animals, preferably to mammals and, inparticular, to humans, as drugs on their own, in mixtures with eachother or in the form of pharmaceutical preparations which permit enteralor parenteral use and which comprise, as the active constituent, aneffective dose of at least one compound of the formula I, or of a saltthereof, together with customary, pharmaceutically unobjectionablecarrier and auxiliary substances. The preparations normally comprisefrom about 0.5 to 90% by weight of the therapeutically active compound.

The drugs may be administered orally, for example in the form of pills,tablets, lacquered tablets, coated tablets, granules, hard and softgelatin capsules, solutions, syrups, emulsions, suspensions or aerosolmixtures. However, the administration can also be effected rectally, forexample in the form of suppositories, or parenterally, for example inthe form of injection or infusion solutions, microcapsules or rods,percutaneously, for example in the form of ointments or tinctures, ornasally, for example in the form of nasal sprays.

The pharmaceutical preparations are produced in a manner known per se,with pharmaceutically inert inorganic or organic carrier substancesbeing used. Lactose, corn starch or derivatives thereof, talc, stearicacid or its salts, etc. can, for example, be used for preparing pills,tablets, coated tablets and hard gelatin capsules. Examples of carriersubstances for soft gelatin capsules and suppositories are fats, waxes,semisolid and liquid polyols, natural or hardened oils, etc. Examples ofsuitable carrier substances for preparing solutions and syrups arewater, sucrose, invert sugar, glucose, polyols, etc. Suitable carriersubstances for preparing injection solutions are water, alcohols,glycerol, polyols, vegetable oils, etc. Suitable carrier substances formicrocapsules, implants or rods are mixed polymers of glycolic acid andlactic acid.

In addition to the active compounds and carrier substances, thepharmaceutical preparations may also comprise additives, such asfillers, extenders, disintegrants, binders, glidants, wetting agents,stabilizers, emulsifiers, preservatives, sweeteners, dyes, flavorants oraromatizing substances, thickeners, diluents or buffering substances,and also solvents or solubilizing agents or agents for achieving a slowrelease effect, and also salts for altering the osmotic pressure,coating agents or antioxidants. They may also comprise two or morecompounds of the formula I or their physiologically tolerated salts;they may furthermore comprise one or more different therapeuticallyactive compounds in addition to at least one compound of the formula I.

The dose may be varied within wide limits and must be adjusted to theindividual circumstances in each individual case.

In the case of oral administration, the daily dose may be from 0.01 to100 mg/kg, preferably from 0.1 to 5 mg/kg, particularly from 0.3 to 0.5mg/kg of bodyweight in order to achieve effective results. In the caseof intravenous administration the daily dose also is generally fromabout 0.01 to 100 mg/kg, preferably from 0.05 to 10 mg/kg of bodyweight.Particularly when administering relatively large quantities, the dailydose can be subdivided into several, e.g. 2, 3 or 4, parts which areadministered separately. Where appropriate, it can be necessary todepart from the given daily dose in an upward or downward directiondepending on the individual response.

Besides as active drug substances the compounds of the formula I may beused in diagnostic procedures, for example in in vitro diagnoses, or astools in biochemical research when it is intended to inhibit thevitronectin receptor.

The inhibition of bone resorption by the novel compounds can bedetermined, for example, using an osteoclast resorption test (PITASSAY), for example in analogy with WO 95132710. The test methods whichcan be used to determine the antagonistic effect of the novel compoundson the vitronectin receptor α_(v)β₃ are described below.

Test Method 1:

Inhibition of the binding of human vitronectin (Vn) to human vitronectinreceptor (VnR) α_(v)β₃: ELISA test.

1. Purification of human vitronectin

Human vitronectin is isolated from human plasma and purified by affinitychromatography using the method of Yatohyo et al., Cell Structure andFunction, 1988, 23, 281-292.

2. Purification of human vitronectin receptor (α_(v)β₃)

Human vitronectin receptor is isolated from the human placenta using themethod of Pytela et al., Methods Enzymol. 1987, 144, 475. Humanvitronectin receptor α_(v)β₃ can also be isolated from some cell lines(e.g. from 293 cells, which is a human embryonic kidney cell line) whichhave been cotransfected with DNA sequences for both the subunits, i.e.α_(v) and β₃, of the vitronectin receptor. The subunits are extractedwith octyl glycoside and then chromatographed through concanavalin A,heparin—Sepharose and S-300.

3. Monoclonal antibodies

Murine monoclonal antibodies which are specific for the β₃ subunit ofthe vitronectin receptor are prepared using the method of Newman et al.,Blood, 1985, 227-232, or using a similar method. Horseradishperoxidase-conjugated rabbit Fab 2 anti-mouse Fc (anti-mouse Fc HRP) wasobtained from Pel Freeze (Catalog No. 715 305-1).

4. ELISA test

Nunc Maxisorp 96-well microtiter plates are coated at 4° C. overnightwith a solution of human vitronectin (0.002 mg/ml, 0.05 ml/well) in PBS(phosphate-buffered sodium chloride solution). The plates are washedtwice with PBS/0.05% Tween 20 and blocked by incubating (60 min) withbovine serum albumin (BSA, 0.5%, RIA quality or better) in Tris-HCl (50mM), NaCl (100 mM), MgCl₂ (1 mM), CaCl₂ (1 mM), MnCl₂ (1 mM), pH 7.Solutions of known inhibitors and of the test substances, inconcentrations of from 2×10⁻¹² to 2×10⁻⁶ mol/l, are prepared in assaybuffer [BSA (0.5%, RIA quality or better) in Tris-HCl (50 mM), NaCl (100mM), MgCl₂ (1 mM), CaCl₂ (1 mM), MnCl₂ (1 mM), pH 7]. The blocked platesare emptied and in each case 0.025 ml of this solution, which contains adefined concentration (from 2×10⁻¹² to 2×10⁻⁶) of either a knowninhibitor or of a test substance, is added to each well. 0.025 ml of asolution of the vitronectin receptor in the test buffer (0.03 mg/ml) ispipetted into each well of the plate and the plate is incubated on ashaker at room temperature for 60-180 min. In the meantime, a solution(6 ml/plate) of a murine monoclonal antibody which is specific for theβ₃ subunit of the vitronectin receptor is prepared in the assay buffer(0.0015 mg/ml). A second rabbit antibody, which is an anti-mouse Fc HRPantibody conjugate, is added to this solution (0.001 ml of stocksolution/6 ml of the murine monoclonal anti-β₃ antibody solution), andthis mixture composed of murine anti-β₃ antibody and rabbit anti-mouseFc HRP antibody conjugate is left to incubate during the period of thereceptor/inhibitor incubation.

The test plates are washed 4 times with PBS solution containing 0.05%Tween-20, and in each case 0.05 ml/well of the antibody mixture ispipetted into each well of the plate and the plate is incubated for60-180 min. The plate is washed 4 times with PBS/0.05% Tween-20 and thendeveloped with 0.05 ml/well of a PBS solution which contains 0.67 mg/mlo-phenylenediamine and 0.012% H₂O₂. As an alternative,o-phenylenediamine can be used in a buffer (pH 5) which contains Na₃PO₄(50 mM) and citric acid. The color development is stopped with 1N H₂SO4(0.05 ml/well). The absorption of each well is measured at 492-405 nmand the data are evaluated using standard methods.

Test Method 2:

Inhibition of the binding of kistrin to human vitronectin receptor (VnR)α_(v)β₃: ELISA test

1. Purification of kistrin

Kistrin is purified using the methods of Dennis et al., as described inProc. Natl. Acad. Sci. USA 1989, 87, 2471-2475 and PROTEINS: Structure,Function and Genetics 1993, 15, 312-321.

2. Purification of human vitronectin receptor (α_(v)β₃) see test method1.

3. Monoclonal antibodies

see test method 1.

4. ELISA test

The ability of substances to inhibit the binding of kistrin to thevitronectin receptor can be ascertained using an ELISA test. For thispurpose, Nunc 96-well microtiter plates are coated with a solution ofkistrin (0.002 mg/ml) using the method of Dennis et al., as described inPROTEINS: Structure, Function and Genetics 1993, 15, 312-321. Thesubsequent experimental implementation of the ELISA test is as describedin test method 1, item 4.

Test Method 3:

Inhibition of the binding of α_(v)β₃-transfected 293 cells to humanvitronectin:

Cell Test

293 cells, a human embryonic kidney cell line, which are cotransfectedwith DNA sequences for the α_(v) and β₃ subunits of the vitronectinreceptor α_(v)β₃ are selected for a high rate of expression (>500,000α_(v)β₃ receptors/cell) using the FACS method. The selected cells arecultured and re-sorted by FACS in order to obtain a stable cell line (15D) having expression rates of >1,000,000 copies of α_(v)β₃ per cell.

A Limbro 96-well tissue culture plate having a flat bottom is coated at4° C. overnight with human vitronectin (0.01 mg/ml, 0.05 ml/well) inphosphate-buffered sodium chloride solution (PBS) and then blocked with0.5% BSA. Solutions of the test substances having concentrations of from10¹⁰ to 2×10⁻³ mol/l are prepared in glucose-containing DMEM medium, andin each case 0.05 ml/well of the solution is added to the plate. Thecells which are expressing high levels of α_(v)β₃ (e.g. 15 D) aresuspended in glucose-containing DMEM medium and the suspension isadjusted to a content of 25,000 cells/0.05 ml of medium. 0.05 ml of thiscell suspension is then added to each well and the plate is incubated at37° C. for 90 min. The plate is washed 3× with warm PBS in order toremove unbound cells. The bound cells are lysed in citrate buffer (25mM, pH 5.0) containing 0.25% Triton X-100. The hexose amidase substratep-nitrophenyl-N-acetyl-β-D-glucosaminide is then added and the plate isincubated at 37° C. for 90 min. The reaction is stopped with a glycine(50 mM)/EDTA (5 mM) buffer (pH 10.4) and the absorption of each well ismeasured at 405-650 nm.

The antagonistic effect of the compounds of the present invention on thefibrinogen receptor α_(IIb)β₃, in particular for determiningselectivity, can be ascertained as described in U.S. Pat. No. 5,403,836,p. 237.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to the compounds, compositionsand processes of this invention. Thus, it is intended that the presentinvention cover such modifications and variations, provided they comewithin the scope of the appended claims and their equivalents.

The disclosure or all publications cited above are expresslyincorporated herein by reference in their entireties to the same extentas if each were incorporated by reference individually. The disclosureof German Patent Application No. 196 53 645.6, is incorporated herein inits entirety.

What is claimed is:
 1. A compound of formula 1, A—B—D—E—F—G  (1) inwhich: A is

is a 5-membered to 10-membered monocyclic or polycyclic, aromatic ornonaromatic ring system which can contain from 1 to 4 heteroatomsselected from the group consisting of N, O and S and can optionally besubstituted, once or more than once, by R¹², R¹³, R¹⁴ and R¹⁵, B is adirect linkage, (C₁-C₈)-alkanediyl,(C₅-C₁₀)-arylene,(C₃-C₈)-cycloalkylene, —C≡C—, —NR²—, —NR²—C(O)—, —NR²—C(O)—NR²—,NR²—C(S)—NR²—, —O—C(O)—, —NR²—S(O)—, —NR²—S(O)₂—, —O—, —S— or —CR²═CR³—,which can in each case be substituted, once or twice, by (C₁-C₈)-alkyl;D is a direct linkage, (C₁-C₈)-alkanediyl, (C₅-C₁₀)-arylene —O—, —NR²—,—CO—NR²—, NR²—CO—, —NR²—C(O)—NR²—, —NR²—C(S)—NR²—, —OC(O)—, —C(O)O—,—S(O)—, —S(O)₂—, —S(O)₂—NR²—, S(O)—NR²—, —NR²—S(O)—, —NR²—S(O)₂—, S—,—CR²═CR³— or —C≡C— which can in each case be substituted, once or twice,by (C₁-C₈)-alkyl, —CR²═CR³— or (C₅-C₆)-aryl, provided that D is not—CO—NR²—, —C(O)O—, —S(O)—, —S(O)₂—, —S(O)—NR²— or —S(O)₂—NR²— when B isa direct linkage; E is

where: R^(1a) and R^(2a) are, independently of each other, from one tothree groups selected from the series consisting of hydrogen, halogen,cyano, carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro,ureido, thioureido, hydroxyl, mercapto or sulfonamido, and an optionallysubstituted radical selected from the group consisting of C₁-C₁₂-alkyl,C₂-C₁₂-alkenyl, C₃-C₁₂-alkynyl, C₃-C₁₂-cycloalkyl, C₆-C₁₄-aryl,C₆-C₁₀-aryl-C₁-C₈-alkyl, C₁-C₁₂-alkyloxy, C₆-C₁₄-aryloxy andC₁-C₁₂-acylamino, where the substituents are a radical selected from thegroup consisting of halogen, cyano, azido, nitro, hydroxyl, mercapto,sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy,formyl, C₁-C₄-alkoxy, phenyl and phenoxy; R^(20a) is hydrogen, halogen,C₁-C₄-alkoxy, C₁-C₄-alkyl, phenyl, benzyl or halogen-C₁-C₄-alkyl, andR^(22b) is: (i) hydrogen (ii) (C₁-C₁₂)-alkyl (iii) (C₆-C₁₄)-aryl (iv)(C₃-C₁₄)-cycloalkyl (v) (C₁-C₁₂)-alkyl-(C₆-C₁₄)-aryl, (vi)(C₁-C₁₂)-alkyl-(C₃-C₁₄)-cycloalkyl, where the radicals defined under(ii) to (vi) can be substituted by one or more radicals selected fromthe group consisting of halogen; nitro; hydroxyl; carboxyl; tetrazole;hydroxamate; sulfonamide; trifluoroimide; phosphonate; C₁-C₆-alkyl;C₆-C₁₄-aryl; benzyl; C₃-C₁₄-cycloalkyl; COR^(24a) and CONR²⁵R²⁶; whereR^(24a) is a radical selected from the group consisting of C₁-C₈-alkoxy;C₃-C₁₂-alkenoxy; C₆-C₁₂-aryloxy; di-C₁-C₈-alkylamino-C₁-C₈-alkoxy;acylamino-C₁-C₈-alkoxy; acetylaminoethoxy; nicotinoylaminoethoxy;succinamidoethoxy; pivaloylethoxy; and C₆-C₁₂-aryl-C₁-C₈-alkoxy, wherethe aryl group can optionally be substituted by from one to threeradicals selected from the group consisting of nitro, halogen,C₁-C₄-alkoxy, amino, hydroxyl, hydroxy-C₂-C₈-alkoxy anddihydroxy-C₃-C₈-alkoxy; R²⁵ and R²⁶ are, independently of each other,hydrogen, C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₆-C₁₄-aryl orC₁-C₆-alkyl-C₆-C₁₀-aryl, or R²⁵ and R²⁶ together form a trimethylene,tetramethylene, pentamethylene or 3-oxopentamethylene radical; or (vii)Q²—L³, where Q² is hydrogen or Q¹; and L³ is a direct linkage, L¹ or L²;Q¹ is a substituted or unsubstituted, positively charged,nitrogen-containing radical; L¹ is a divalent radical which containsfrom 3 to 9 methylene groups, where from one to all the methylene groupscan be replaced with one or more alkene radicals, alkyne radicals, arylradicals or heteroatoms selected from the group consisting of N, O andS, and amide group, and L² is an optionally substituted, divalentradical; F is defined like D; G is

wherein R² and R³ are, independently of each other, hydrogen,(C₁-C₁₀)-alkyl, which is optionally substituted, once or more than once,by fluorine, (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl,(C₅-C₁₄)-aryl, (C₅-C₁₄)-aryl-(C₁-C₈)-alkyl, R⁸OC(O)R⁹, R⁸R⁸NC(O)R⁹ orR⁸C(O)R⁹; R⁴, R⁵, R⁶ and R⁷ are, independently of each other, hydrogen,fluorine, OH, (C₁-C₈)-alkyl, (C₃-C₁₄)-cycloalkyl,(C₃-C₁₄)-cycloalkyl-(C₁-C₈)-alkyl, or R⁸OR⁹, R⁸SR⁹, R⁸CO₂R⁹, R⁸OC(O)R⁹,R⁸—(C₅-C₁₄)-aryl-R⁹, R⁸N(R²)R⁹, R⁸R⁸NR⁹,R⁸N(R²)C(O)OR⁹,R⁸S(O)_(n)N(R²)R⁹, R⁸OC(O)N(R²)R⁹, R⁸C(O)N(R²)R⁹,R⁸N(R²)C(O)N(R²)R⁹, R⁸N(R²)S(O)_(n)N(R²)R⁹, R⁸S(O)_(n)R⁹,R⁸SC(O)N(R²)R⁹, R⁸C(O)R⁹, R⁸N(R²)C(O)R⁹ or R⁸N(R²)S(O)_(n)R⁹; R⁸ ishydrogen, (C₁-C₈)-alkyl, (C₃-C₁₄)-cycloalkyl,(C₃-C₁₄)-cycloalkyl-(C₁-C₈)-alkyl, (C₅-C₁₄)-aryl or(C₅-C₁₄)-aryl-(C₁-C₈)-alkyl, where the alkyl radicals can besubstituted, once or more than once, by fluorine; R⁹ is a direct linkageor (C₁-C₈)-alkanediyl; R¹⁰ is C(O)R¹¹, C(S)R¹¹, S(O)_(n)R¹¹, P(O)(R¹¹)₂or a four-membered to eight-membered, saturated or unsaturatedheterocycle which contains 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S; R¹¹ is OH, (C₁-C₈)-alkoxy,(C₅-C₁₄)-aryl-(C₁-C₈)-alkoxy, (C₅-C₁₄)-aryloxy,(C₁-C₈)-alkylcarbonyloxy-(C₁-C₄)-alkoxy,(C₅-C₁₄)-aryl-(C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxy, NH₂, mono- ordi-((C₁-C₈)-alkyl)-amino, (C₅-C₁₄)-aryl-(C₁-C₈)-alkylamino,(C₁-C₈)-dialkylaminocarbonylmethyloxy,(C₅-C₁₄)-aryl-(C₁-C₈)-dialkylaminocarbonylmethyloxy or(C₅-C₁₄)-arylamino or the radical of an L-amino acid or D-amino acid;R¹², R¹³, R¹⁴ and R¹⁵ are, independently of each other, hydrogen,(C₁-C₁₀)-alkyl which is optionally substituted, once or more than once,by fluorine, (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl,(C₅-C₁₄)-aryl, (C₅-C₁₄)-aryl-(C₁-C₈)-alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹,R⁸OC(O)R⁹, R⁸R⁸NR⁹, R⁸—(C₅-C₁₄)-aryl-R⁹, HO—(C₁-C₈)alkyl-N(R²)R⁹,R⁸N(R²)C(O)R⁹, R⁸C(O)N(R²)R⁹, R⁸C(O)R⁹, R²R³N—C(═NR²)—NR²,R²R³N—C(═NR²), ═O, or ═S; where two adjacent substituents from R¹² toR¹⁵ can also together be —OCH₂O—, —OCH₂CH₂O— or —OC(CH₃)₂O—; Y is NR², Oor S; n is 1 or 2; p and q are, independently of each other, 0 or 1; inall its stereoisomeric forms and mixtures thereof in all proportions,and its physiologically tolerated salts.
 2. A compound of the formula 1as claimed in claim 1, in which: A is the radial

Is a 5-membered to 10-membered monocyclic or polycyclic, aromatic ornonaromatic ring system which can contain from 1 to 4 heteroatomsselected from the group consisting of N, O and S and which canoptionally be substituted, once or more than once, by R¹², R¹³, R¹⁴ andR¹⁵. B is a direct linkage, (C₁-C₆)-alkanediyl, (C₅-C₈)-arylene,(C₃-C₈)-cycloalkylene, —C≡C—, —NR²—, —NR²—C(O)—, —NR²—C(O)—NR²—,—NR²—S(O)—, —NR²—S(O)₂—, —O— or —CR²═CR³— which can in each case besubstituted, once or twice, by (C₁-C₆)-alkyl; D is a direct linkage,(C₁-C₈)-alkanediyl, (C₅-C₈)-arylene, —O—, —NR²—, —CO—NR²—, —NR²—CO—,—NR²—C(O)—NR²—, —OC(O)—, —C(O)O—, —S(O)₂—, —S(O)₂—NR²—, —NR²—S(O)₂—,—S—, —CR²═CR³— or —C≡C— which can in each case be substituted, once ortwice, by (C₁-C₈)-alkyl, —CR²═CR³— or (C₅-C₆)-aryl, provided that D isnot —CO—NR²—, —C(O)O—, —SO₂— or —S(O)₂—NR²— when B is a direct linkage;F is defined like D; G is

R² and R³ are, independently of each other, hydrogen, (C₁-C₁₀)-alkyl,which is optionally substituted, once or more than once, by fluorine,(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₆)-alkyl, (C₅-C₁₂)-aryl,(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl, R⁸OC(O)R⁹, R⁸R⁸NC(O)R⁹ or R⁸C(O)R⁹; R⁴, R⁵,R⁶ and R⁷ are, independently of each other, hydrogen, fluorine, OH,(C₁-C₈)-alkyl, (C₅-C₁₄)-cycloalkyl, (C₅-C₁₄)-cycloalkyl-(C₁-C₈)-alkyl,or R⁸OR⁹, R⁸SR⁹, R⁸CO₂R⁹, R⁸OC(O)R⁹, R⁸—(C₅-C₁₄)-aryl-R⁹, R⁸N(R²)R⁹,R⁸R⁸NR⁹, R⁸N(R²)C(O)OR⁹, R⁸S(O)_(n)N(R²)R⁹, R⁸OC(O)N(R²)R⁹,R⁸C(O)N(R²)R⁹, R⁸N(R²)C(O)N(R²)R⁹, R⁸N(R²)S(O)_(n)N(R²)R⁹, R⁸S(O)_(n)R⁹,R⁸SC(O)N(R²)R⁹, R⁸C(O)R⁹, R⁸N(R²)C(O)R⁹ or R⁸N(R²)S(O)_(n)R⁹; R⁸ ishydrogen, (C₁-C₈)-alkyl, (C₅-C₁₄)-cycloalkyl,(C₅-C₁₄)-cycloalkyl-(C₁-C₆)-alkyl, (C₅-C₁₂)-aryl or(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl, where the alkyl radicals can besubstituted, once or more than once, by fluorine; R⁹ is a direct linkageor (C₁-C₆)-alkanediyl; R¹⁰ is C(O)R¹¹, C(S)R¹¹, S(O)_(n)R¹¹, P(O)(R¹¹)₂or a four-membered to eight-membered, saturated or unsaturatedheterocycle which contains 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S; R¹¹ is OH, (C₁-C₆)-alkoxy,(C₅-C₁₂)-aryl-(C₁-C₆)-alkoxy, (C₅-C₁₂)-aryloxy,(C₁-C₆)-alkylcarbonyloxy-(C₁-C₄)-alkoxy,(C₅-C₁₂)-aryl-(C₁-C₆)-alkylcarbonyloxy-(C₁-C₆)-alkoxy, NH₂, mono- ordi-((C₁-C₆)-alkyl)-amino, (C₅-C₁₂)-aryl-(C₁-C₆)-alkylamino,(C₁-C₆)-dialkylaminocarbonylmethyloxy; R¹², R¹³, R¹⁴ and R¹⁵ are,independently of each other, hydrogen, (C₁-C₈)-alkyl which is optionallysubstituted, once or more than once, by fluorine, (C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₆)-alkyl, (C₅-C₁₂)-aryl,(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹, R⁸OC(O)R⁹, R⁸R⁸NR⁹,R⁸—(C₅-C₁₂)-aryl-R⁹, R⁸R⁸NR⁹, HO—(C₁-C₈)-alkyl-N(R²)R⁹, R⁸N(R²)C(O)R⁹,R⁸C(O)N(R²)R⁹, R⁸C(O)R⁹, R²R³N—C(═NR²), R²R³N—C(═NR²)—NR², ═O, or ═S;where two adjacent substituents from R¹² to R¹⁵ can also together be—OCH₂O——OCH₂CH₂O— or —OC(CH₃)₂O—; Y is NR², O or S; p and q are,independently of each other, 0 or 1; and E is as defined in claim 1; inall its stereoisomeric forms and mixtures thereof in all proportions,and its physiologically tolerated salts.
 3. A compound of the formula 1as claimed in claim 1, in which: A is one of the radicals

B is a direct linkage, (C₁-C₆)-alkanediyl, (C₅-C₆)-arylene,(C₅-C₆)-cycloalkylene, —C≡C—, —NR²—, —NR²—C(O)—, —NR²—S(O)₂—, —O— or—CR²═CR³—, which can in each case be substituted, once or twice, by(C₁-C₆)-alkyl; D is a direct linkage, (C₁-C₆)-alkanediyl,(C₅-C₆)-arylene, —O—, —NR²—, —NR²—C(O)—, —C(O)NR²—, —NR²—C(O)—NR²—,—OC(O)—, —S(O)₂—NR²—, —NR²—S(O)₂— or —CR²═C³— which can in each case besubstituted, once or twice, by (C₁-C₆)-alkyl, provided that D is not—C(O)NR²— or —S(O)₂—NR²— when B is a direct linkage; E is defined as inclaim 1; F is a direct linkage, (C₁-C₆)-alkanediyl, —O—, —CO—NR²—,—NR²—CO—, —NR²—C(O)—NR²—, —OC(O)—, —C(O)O—, —S(O)₂—, —S(O)₂—NR²—,—NR²—S(O)₂—, —CR²═CR³—, or —C≡C— which can in each case be substituted,once or twice, by (C₁-C₆)-alkyl; and G is

wherein R₂ and R₃ are, independently of each other, hydrogen,(C₁-C₆)-alkyl which is optionally substituted, once or more than once,by fluorine, (C₅-C₆)-cycloalkyl, (C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl,(C₅-C₁₀)-aryl, (C₅-C₁₀)-aryl-(C₁-C₄)-alkyl, R⁸OC(O)R⁹, R⁸R⁸NC(O)R⁹ orR⁸C(O)R⁹; R⁴, R⁵, R⁶ and R⁷ are, independently of each other, hydrogen,fluorine, OH, (C_(1-C) ₆)-alkyl, (C₅-C₁₄)-cycloalkyl,(C₅-C₁₄)-cycloalkyl-(C₁-C₆)-alkyl, or R⁸OR⁹, R⁸CO₂R⁹, R⁸OC(O)R⁹,R⁸—(C₅-C₁₀)-aryl-R⁹, R⁸NHR⁹, R⁸R⁸NR⁹, R⁸NHC(O)OR⁹, R⁸S(O)_(n)NHR⁹,R⁸OC(O)NHR⁹, R⁸C(O)NHR⁹, R⁸C(O)R⁹, R⁸NHC(O)NHR⁹, R⁸NHS(O)_(n)NHR⁹,R⁸NHC(O)R⁹ or R⁸NHS(O)_(n)R⁹, where are least one of the groups R⁴, R⁵,R⁶ and R⁷ is a lipophilic radical; R⁸ is hydrogen, (C₁-C₆)-alkyl,(C₅-C₁₄)-cycloalkyl, (C₅-C₁₄)-cycloalkyl-(C₁-C₄)-alkyl, (C₅-C₁₀)-aryl or(C₅-C₁₀)-aryl-(C₁-C₄)-alkyl, where the alkyl radicals can be substitutedby from 1 to 6 fluorine atoms; R⁹ is a direct linkage or(C₁-C₆)-alkanediyl; R¹⁰ is C(O)R¹¹; R¹¹ is OH, (C₁-C₆)-alkoxy,(C₅-C₁₀)-aryl-(C₁-C₆)-alkoxy, (C₅-C₁₀)-aryloxy,(C₁-C₆)-alkylcarbonyloxy-(C₁-C₄)-alkoxy,(C₅-C₁₀)-aryl-(C₁-C₄)-alkylcarbonyloxy-(C₁-C₄)-alkoxy, NH₂ or mono- ordi-((C₁-C₆)-alkyl)-amino; R¹² is hydrogen, (C₁-C₆)-alkyl which isoptionally substituted, once or more than once, by fluorine,(C₃-C₆)-cycloalkyl, (C₃-C₆)-cycloalkyl-(C₁-C₄)-alkyl, (C₅-C₁₀)-aryl,(C₅-C₁₀)-aryl-(C₁-C₄)-alkyl, H₂N, R⁸OR⁹, R⁸OC(O)R⁹, R⁸—(C₅-C₁₀)-aryl-R⁹,R⁸R⁸NR⁹, R⁸NHC(O)R⁹, R⁸C(O)NHR⁹, H₂N—C(═NH)—, H₂N—C(═NH)—NH— or ═O;where two adjacent substituents R¹² can together also be —OCH₂O— or—OCH₂CH₂O—; Y is NR₂, O or S; n is 1 or 2; and p and q are,independently of each other, 0 or 1; in all its stereoisomeric forms andmixtures thereof in all proportions, and its physiologically toleratedsalts.
 4. A compound of the formula 1 as claimed in claim 1, in which: Ais one of the radicals

B is a direct linkage, (C₁-C₄)-alkanediyl, phenylene, pyridindiyl,thiophenediyl, furandiyl, cyclohexylene, cyclopentylene, —C≡C— or—CR²═CR³— which can in each case be substituted, once or twice, by(C₁-C₄)-alkyl; D is a direct linkage, (C₁-C₄)-alkanediyl, phenylene,—O—, —NR²—, —NR²—C(O)—, —C(O)—NR²—, —NR²—S(O)₂, —NR²—C(O)—NR²— or—CR²═CR³— which can in each case be substituted, once or twice, by(C₁-C₄)-alkyl, provided that D is not —C(O)—NR²— when B is a directlinkage; E a) is

where: R^(1a) is, independently of each other, selected from one tothree groups selected from the series consisting of hydrogen andhalogen; R^(20a) is hydrogen; R^(22b) is (i) hydrogen (ii)(C₁-C₁₂)-alkyl, (iii) (C₆-C₁₄)-aryl, (iv) (C₃-C₁₄)-cycloalkyl, (v)(C₁-C₁₂)-alkyl-(C₆-C₁₄)-aryl, (vi) (C₁-C₁₂)-alkyl-(C₃-C₁₄)-cycloalkyl,where the radicals defined under (ii) to (vi) can be substituted by oneor more radicals selected from the group consisting of halogen; nitro;hydroxyl; carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide;phosphonate; C₁-C₆-alkyl; C₆-C₁₄-aryl; benzyl; C₃-C₁₄-cycloalkyl;COR^(24a) and CONR²⁵R²⁶; where R^(24a) is a radical selected from thegroup consisting of C₁-C₈-alkoxy; C₃-C₁₂-alkenoxy; C₆-C₁₂-aryloxy;di-C₁-C₈-alkylamino-C₁-C₈-alkoxy; acylamino-C₁-C₈-alkoxy;acetylaminoethoxy; nicotinoylaminoethoxy; succinamidoethoxy;pivaloylethoxy; and C₆-C₁₂-aryl-C₁-C₈-alkoxy, where the aryl group canbe optionally substituted by from one to three radicals selected fromthe group consisting of nitro, halogen, C₁-C₄-alkoxy, amino, hydroxyl,hydroxy-C₂-C₈-alkoxy and dihydroxy-C₃-C₈-alkoxy; R²⁵ and R²⁶ are,independently of each other, hydrogen C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl,C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, or R²⁵ and R²⁶ together form atrimethylene, tetramethylene, pentamethylene or 3-oxopentamethyleneradical; or (vii) Q²—L³, where Q² is hydrogen or Q¹; and L³ is a directlinkage or L¹; Q¹ is an amino, amidino, aminoalkylenimino,iminoalkylenamino or guanidino group; L¹ isC₆-C₁₄-aryl-C₂-C₄-alkynylene; C₆-C₁₄-aryl-C₁-C₃-alkylene;C₆-C₁₄-aryl-C₁-C₃-alkyloxyene or —R^(14c)—CO—NR^(6c)R^(15c), whereR^(6c) is hydrogen, C₁-C₄-alkoxy, C₁-C₄-alkyl or halogen-C₁-C₄-alkyl;R^(14c) is a direct linkage, C₁-C₈-alkylene, C₃-C₇-cycloalkylene,C₂-C₅-alkenylene, C₃-C₅-alkynylene, C₆-C₁₀-arylene,C₁-C₃-alkyl-C₆-C₁₂-arylene, C₁-C₂-alkyl-C₆-C₁₀-aryl-C₁-C₂-alkylene,C₆-C₁₀-aryl-C₁-C₂-alkylene or C₆-C₁₀-aryloxy-C₁-C₂-alkylene, and R^(15c)is a chemical bond, C₁-C₄-alkylene, C₂-C₄-alkenylene, C₂-C₄-alkynylene,C₆-C₁₀-arylene or C₁-C₃-alkyl-C₆-C₁₂-arylene; F is a direct linkage,(C₁-C₆)-alkanediyl, —O—, —CO—NR²—, —NR²—CO—, —NR²—C(O)—NR²—, —S(O)₂—NR²,—NR²—S(O)₂—, —CR²═CR³—, or —C≡C— which can in each case be substituted,once or twice, by (C₁-C₄)-alkyl; G is

wherein: R² and R³ are, independently of each other, hydrogen,—(C₁-C₄)-alkyl, trifluoromethyl, pentafluoroethyl, (C₅-C₆)-cycloalkyl,(C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl, phenyl or benzyl; R⁴ is(C₁₀-C₁₄)-cycloalkyl, (C₁₀-C₁₄)-cycloalkyl-(C₁-C₄)-alkyl, or R¹⁶OR⁹,R¹⁶NHR⁹, R¹⁶NHC(O)OR⁹, R¹⁶S(O)_(n)—NHR⁹, R¹⁶OC(O)NHR⁹, R¹⁶C(O)NHR⁹,R¹⁶C(O)R⁹, R¹⁶NHC(O)R⁹ or R¹⁶NHS(O)_(n)R⁹; R⁵ is hydrogen,(C₁-C₆)-alkyl, (C₅-C₆)-cycloalkyl, (C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl,trifluoromethyl, pentafluoroethyl, phenyl or benzyl; R⁸ is hydrogen,(C₁-C₄)-alkyl, (C₅-C₆)-cycloalkyl, (C₅-C₆)-cycloalkyl-(C₁-C₂)-alkyl,phenyl, benzyl, trifluoromethyl or pentafluoroethyl; R⁹ is a directlinkage or (C₁-C₄)-alkanediyl; R¹⁰ is C(O)R¹¹; R¹¹ is OH,(C₁-C₆)-alkoxy, phenoxy, benzyloxy,(C₁-C₄)-alkylcarbonyloxy-(C₁-C₄)-alkoxy, NH₂ or mono- ordi-((C₁-C₆)-alkyl)amino; R¹² is hydrogen, (C₁-C₄)-alkyl,trifluoromethyl, pentafluoroethyl, (C₅-C₆)-cycloalkyl,(C₅-C₆)-cycloalkyl-(C₁-C₂)-alkyl, (C₅-C₆)-aryl,(C₅-C₆)-aryl-(C₁-C₂)-alkyl, H₂N, R⁸R⁸NR⁹, R⁸NHC(O)R⁹, H₂N—C(=NH) orH₂N—C(=NH)—NH—; where two adjacent substituents R¹² can also be —OCH₂O—or —OCH₂CH₂O—; R¹⁶ is (C₁₀-C₁₄)-cycloalkyl or(C₁₀-C₁₄)-cycloalkyl-(C₁-C₄)-alkyl; n is 1 or 2; and q is 0 or 1; in allits stereoisomeric forms and mixtures thereof in all proportions, andits physiologically tolerated salts.
 5. A compound of the formula I asclaimed in claim 1, in which the distance between R¹⁰ and the first Natom in A is from 12 to 13 covalent bonds along the shortest routebetween these atoms, in all its stereoisomeric forms and mixturesthereof in all proportions, and its physiologically tolerated salts. 6.A process for preparing a compound of the formula I as claimed in claim1, which comprises linking, by means of fragment condensation, two ormore fragments which can be derived retrosynthetically from the formulaI.
 7. A pharmaceutical preparation, comprising at least one compound ofthe formula I as claimed in claim 1, and/or its physiologicallytolerated salts, in addition to pharmaceutically unobjectionable carrierand auxiliary substances.
 8. A method for the treatment or prophylaxisof osteoporosis comprising administering to a subject in need thereof aneffective amount of at least one compound as claimed in claim
 1. 9. Amethod for the treatment or prophylaxis of cancer comprisingadministering to a subject in need thereof an effective amount of atleast one compound as claimed in claim
 1. 10. A method for inhibitingbone resorption by osteoclasts, inhibiting tumor growth or tumormetastasis, inhibiting inflammation, or for the treatment or prophylaxisof cardiovascular diseases, for the treatment or prophylaxis ofneuropathies or retinopathies, or as a vitronectin receptor antagonistfor the treatment or prophylaxis of diseases which are based on theinteraction between vitronectin receptors and their ligands in cell-cellor cell-matrix interaction processes comprising administering to asubject in need thereof an effective amount of at least one compound asclaimed in claim
 1. 11. A pharmaceutical preparation, comprising atleast one compound of the formula I as claimed in claim 1, and/or itsphysiologically tolerated salts, in addition to at least onepharmaceutically tolerable carrier, excipient, and/or additives.
 12. Thecompound of the formula 1 as claimed in claim 1, wherein R¹⁶ is1-adamantyle or 2-adamantyle.